B. Alberts, A. Johnson, J. Lewis и др. - Molecular Biology of The Cell (6th edition), страница 7

Yamada (NIH), KeithYamamoto (University of California, San Francisco),Charles Yocum (University of Michigan, Ann Arbor), PeterYurchenco (UMDNJ—Robert Wood Johnson MedicalSchool), Rosalind Zalin (University College London),Patricia Zambryski (University of California, Berkeley),Marino Zerial (Max Planck Institute of Molecular CellBiology and Genetics).xixContentsPART IINTRODUCTION TO THE CELL1Chapter 1Cells and Genomes1Chapter 2Cell Chemistry and BioenergeticsChapter 3Proteins109PART IIBASIC GENETIC MECHANISMS173Chapter 4DNA, Chromosomes, and Genomes173Chapter 5DNA Replication, Repair, and Recombination237Chapter 6How Cells Read the Genome: From DNA to Protein299Chapter 7Control of Gene Expression369PART IIIWAYS OF WORKING WITH CELLS439Chapter 8Analyzing Cells, Molecules, and Systems439Chapter 9Visualizing Cells529PART IVINTERNAL ORGANIZATION OF THE CELL565Chapter 10Membrane Structure565Chapter 11Membrane Transport of Small Molecules and the ElectricalProperties of Membranes597Chapter 12Intracellular Compartments and Protein Sorting641Chapter 13Intracellular Membrane Traffic695Chapter 14Energy Conversion: Mitochondria and Chloroplasts753Chapter 15Cell Signaling813Chapter 16The Cytoskeleton889Chapter 17The Cell Cycle963Chapter 18Cell Death1021PART VCELLS IN THEIR SOCIAL CONTEXT1035Chapter 19Cell Junctions and the Extracellular Matrix1035Chapter 20Cancer1091Chapter 21Development of Multicellular Organisms1145Chapter 22Stem Cells and Tissue Renewal1217Chapter 23Pathogens and Infection1263Chapter 24The Innate and Adaptive Immune Systems1297GlossaryG: 1IndexTables43I: 1The Genetic Code, Amino AcidsT: 1xxSpecial FeaturesTABLE 1–2TABLE 2–1TABLE 2–2PANEL 2–1PANEL 2–2PANEL 2–3PANEL 2–4PANEL 2–5PANEL 2–6PANEL 2–7PANEL 2–8PANEL 2–9PANEL 3–1TABLE 3–3TABLE 4–1TABLE 5–4TABLE 6–1PANEL 7–1PANEL 8–1PANEL 8–2TABLE 11–1PANEL 11–1TABLE 12–1PANEL 14–1TABLE 14–1TABLE 15–3TABLE 15–4TABLE 15–5TABLE 15–6PANEL 16–2TABLE 16–1PANEL 16–3PANEL 16–4TABLE 16–2TABLE 17–1TABLE 17–2PANEL 17–1TABLE 19–1TABLE 19–2TABLE 19–3TABLE 22–1TABLE 24–2TABLE 24–3Some Model Organisms and Their GenomesCovalent and Noncovalent Chemical BondsRelationship Between the Standard Free-Energy Change, ΔG°, and the Equilibrium ConstantChemical Bonds and Groups Commonly Encountered in Biological MoleculesWater and Its Influence on the Behavior of Biological MoleculesThe Principal Types of Weak Noncovalent Bonds that Hold Macromolecules TogetherAn Outline of Some of the Types of Sugars Commonly Found in CellsFatty Acids and Other LipidsA Survey of the NucleotidesFree Energy and Biological ReactionsDetails of the 10 Steps of GlycolysisThe Complete Citric Acid CycleThe 20 Amino Acids Found in ProteinsSome Molecules Covalently Attached to Proteins Regulate Protein FunctionSome Vital Statistics for the Human GenomeThree Major Classes of Transposable ElementsPrincipal Types of RNAs Produced in CellsCommon Structural Motifs in Transcription RegulatorsDNA Sequencing MethodsReview of Classical GeneticsA Comparison of Inorganic Ion Concentrations Inside and Outside a Typical Mammalian CellThe Derivation of the Nernst EquationRelative Volumes Occupied by the Major Intracellular Compartments in a Liver Cell (Hepatocyte)Redox PotentialsProduct Yields from the Oxidation of Sugars and FatsFour Major Families of Trimeric G ProteinsSome Signal Proteins That Act Via RTKsThe Ras Superfamily of Monomeric GTPasesSome Extracellular Signal Proteins That Act Through Cytokine Receptors and the JAK–STAT SignalingPathwayThe Polymerization of Actin and TubulinChemical Inhibitors of Actin and MicrotubulesActin FilamentsMicrotubulesMajor Types of Intermediate Filament Proteins in Vertebrate CellsThe Major Cyclins and Cdks of Vertebrates and Budding YeastSummary of the Major Cell Cycle Regulatory ProteinsThe Principle Stages of M Phase (Mitosis and Cytokinesis) in an Animal CellAnchoring JunctionsSome Types of Collagen and Their PropertiesSome Types of IntegrinsBlood CellsProperties of the Major Classes of Antibodies in HumansProperties of Human Class I and Class II MHC Proteins2945639092949698100102104106112165184288305376478486598616643765775846850854864902904905933944969973980103710631076124113181330xxiDetailed ContentsChapter 1 Cells and Genomes1THE UNIVERSAL FEATURES OF CELLS ON EARTHAll Cells Store Their Hereditary Information in the Same LinearChemical Code: DNAAll Cells Replicate Their Hereditary Information by TemplatedPolymerizationAll Cells Transcribe Portions of Their Hereditary Information intothe Same Intermediary Form: RNAAll Cells Use Proteins as CatalystsAll Cells Translate RNA into Protein in the Same WayEach Protein Is Encoded by a Specific GeneLife Requires Free EnergyAll Cells Function as Biochemical Factories Dealing with the SameBasic Molecular Building BlocksAll Cells Are Enclosed in a Plasma Membrane Across WhichNutrients and Waste Materials Must PassA Living Cell Can Exist with Fewer Than 500 GenesSummary2234567888910THE DIVERSITY OF GENOMES AND THE TREE OF LIFECells Can Be Powered by a Variety of Free-Energy SourcesSome Cells Fix Nitrogen and Carbon Dioxide for OthersThe Greatest Biochemical Diversity Exists Among Prokaryotic CellsThe Tree of Life Has Three Primary Branches: Bacteria, Archaea,and EukaryotesSome Genes Evolve Rapidly; Others Are Highly ConservedMost Bacteria and Archaea Have 1000–6000 GenesNew Genes Are Generated from Preexisting GenesGene Duplications Give Rise to Families of Related Genes Withina Single CellGenes Can Be Transferred Between Organisms, Both in theLaboratory and in NatureSex Results in Horizontal Exchanges of Genetic InformationWithin a SpeciesThe Function of a Gene Can Often Be Deduced from Its SequenceMore Than 200 Gene Families Are Common to All Three PrimaryBranches of the Tree of LifeMutations Reveal the Functions of GenesMolecular Biology Began with a Spotlight on E.

coliSummary10101212GENETIC INFORMATION IN EUKARYOTESEukaryotic Cells May Have Originated as PredatorsModern Eukaryotic Cells Evolved from a SymbiosisEukaryotes Have Hybrid GenomesEukaryotic Genomes Are BigEukaryotic Genomes Are Rich in Regulatory DNAThe Genome Defines the Program of Multicellular DevelopmentMany Eukaryotes Live as Solitary CellsA Yeast Serves as a Minimal Model EukaryoteThe Expression Levels of All the Genes of An OrganismCan Be Monitored SimultaneouslyArabidopsis Has Been Chosen Out of 300,000 SpeciesAs a Model PlantThe World of Animal Cells Is Represented By a Worm, a Fly,a Fish, a Mouse, and a HumanStudies in Drosophila Provide a Key to Vertebrate DevelopmentThe Vertebrate Genome Is a Product of Repeated Duplications2324252728292930301415161617181920202122223232333334The Frog and the Zebrafish Provide Accessible Models forVertebrate DevelopmentThe Mouse Is the Predominant Mammalian Model OrganismHumans Report on Their Own PeculiaritiesWe Are All Different in DetailTo Understand Cells and Organisms Will Require Mathematics,Computers, and Quantitative InformationSummaryProblemsReferences3535363838393941Chapter 2 Cell Chemistry and Bioenergetics43THE CHEMICAL COMPONENTS OF A CELLWater Is Held Together by Hydrogen BondsFour Types of Noncovalent Attractions Help Bring MoleculesTogether in CellsSome Polar Molecules Form Acids and Bases in WaterA Cell Is Formed from Carbon CompoundsCells Contain Four Major Families of Small Organic MoleculesThe Chemistry of Cells Is Dominated by Macromolecules withRemarkable PropertiesNoncovalent Bonds Specify Both the Precise Shape of aMacromolecule and Its Binding to Other MoleculesSummaryCATALYSIS AND THE USE OF ENERGY BY CELLSCell Metabolism Is Organized by EnzymesBiological Order Is Made Possible by the Release of Heat Energyfrom CellsCells Obtain Energy by the Oxidation of Organic MoleculesOxidation and Reduction Involve Electron TransfersEnzymes Lower the Activation-Energy Barriers That BlockChemical ReactionsEnzymes Can Drive Substrate Molecules Along Specific ReactionPathwaysHow Enzymes Find Their Substrates: The Enormous Rapidity ofMolecular MotionsThe Free-Energy Change for a Reaction, ∆G, Determines WhetherIt Can Occur SpontaneouslyThe Concentration of Reactants Influences the Free-EnergyChange and a Reaction’s DirectionThe Standard Free-Energy Change, ∆G°, Makes It Possibleto Compare the Energetics of Different ReactionsThe Equilibrium Constant and ∆G° Are Readily Derived fromEach OtherThe Free-Energy Changes of Coupled Reactions Are AdditiveActivated Carrier Molecules Are Essential for BiosynthesisThe Formation of an Activated Carrier Is Coupled to anEnergetically Favorable ReactionATP Is the Most Widely Used Activated Carrier MoleculeEnergy Stored in ATP Is Often Harnessed to Join Two MoleculesTogetherNADH and NADPH Are Important Electron CarriersThere Are Many Other Activated Carrier Molecules in CellsThe Synthesis of Biological Polymers Is Driven by ATP HydrolysisSummaryHOW CELLS OBTAIN ENERGY FROM FOODGlycolysis Is a Central ATP-Producing PathwayFermentations Produce ATP in the Absence of Oxygen434444454747474950515152545557585960616162636364656567687073737475xxiiDETAILED CONTENTSGlycolysis Illustrates How Enzymes Couple Oxidation to EnergyStorageOrganisms Store Food Molecules in Special ReservoirsMost Animal Cells Derive Their Energy from Fatty Acids BetweenMealsSugars and Fats Are Both Degraded to Acetyl CoA in MitochondriaThe Citric Acid Cycle Generates NADH by Oxidizing AcetylGroups to CO2Electron Transport Drives the Synthesis of the Majority of the ATPin Most CellsAmino Acids and Nucleotides Are Part of the Nitrogen CycleMetabolism Is Highly Organized and RegulatedSummaryProblemsReferencesChapter 3 ProteinsTHE SHAPE AND STRUCTURE OF PROTEINSThe Shape of a Protein Is Specified by Its Amino Acid SequenceProteins Fold into a Conformation of Lowest EnergyThe α Helix and the β Sheet Are Common Folding PatternsProtein Domains Are Modular Units from Which Larger ProteinsAre BuiltFew of the Many Possible Polypeptide Chains Will Be Usefulto CellsProteins Can Be Classified into Many FamiliesSome Protein Domains Are Found in Many Different ProteinsCertain Pairs of Domains Are Found Together in Many ProteinsThe Human Genome Encodes a Complex Set of Proteins,Revealing That Much Remains UnknownLarger Protein Molecules Often Contain More Than OnePolypeptide ChainSome Globular Proteins Form Long Helical FilamentsMany Protein Molecules Have Elongated, Fibrous ShapesProteins Contain a Surprisingly Large Amount of IntrinsicallyDisordered Polypeptide ChainCovalent Cross-Linkages Stabilize Extracellular ProteinsProtein Molecules Often Serve as Subunits for the Assemblyof Large StructuresMany Structures in Cells Are Capable of Self-AssemblyAssembly Factors Often Aid the Formation of Complex BiologicalStructuresAmyloid Fibrils Can Form from Many ProteinsAmyloid Structures Can Perform Useful Functions in CellsMany Proteins Contain Low-complexity Domains that Can Form“Reversible Amyloids”SummaryPROTEIN FUNCTIONAll Proteins Bind to Other MoleculesThe Surface Conformation of a Protein Determines Its ChemistrySequence Comparisons Between Protein Family MembersHighlight Crucial Ligand-Binding SitesProteins Bind to Other Proteins Through Several Types ofInterfacesAntibody Binding Sites Are Especially VersatileThe Equilibrium Constant Measures Binding StrengthEnzymes Are Powerful and Highly Specific CatalystsSubstrate Binding Is the First Step in Enzyme CatalysisEnzymes Speed Reactions by Selectively Stabilizing TransitionStatesEnzymes Can Use Simultaneous Acid and Base CatalysisLysozyme Illustrates How an Enzyme WorksTightly Bound Small Molecules Add Extra Functions to ProteinsMultienzyme Complexes Help to Increase the Rate of CellMetabolismThe Cell Regulates the Catalytic Activities of Its EnzymesAllosteric Enzymes Have Two or More Binding Sites That InteractTwo Ligands Whose Binding Sites Are Coupled Must ReciprocallyAffect Each Other’s BindingSymmetric Protein Assemblies Produce Cooperative AllostericTransitionsMany Changes in Proteins Are Driven by Protein PhosphorylationA Eukaryotic Cell Contains a Large Collection of Protein Kinasesand Protein Phosphatases76788181828485878888108109109109114115117118119121122122123123124125127127128130130132132134134134135136137138138140141141144144146148149151151152153154The Regulation of the Src Protein Kinase Reveals How a ProteinCan Function as a MicroprocessorProteins That Bind and Hydrolyze GTP Are Ubiquitous CellRegulatorsRegulatory Proteins GAP and GEF Control the Activity of GTPBinding Proteins by Determining Whether GTP or GDPIs BoundProteins Can Be Regulated by the Covalent Addition of OtherProteinsAn Elaborate Ubiquitin-Conjugating System Is Used to MarkProteinsProtein Complexes with Interchangeable Parts Make EfficientUse of Genetic InformationA GTP-Binding Protein Shows How Large Protein MovementsCan Be GeneratedMotor Proteins Produce Large Movements in CellsMembrane-Bound Transporters Harness Energy to PumpMolecules Through MembranesProteins Often Form Large Complexes That Function as ProteinMachinesScaffolds Concentrate Sets of Interacting ProteinsMany Proteins Are Controlled by Covalent Modifications ThatDirect Them to Specific Sites Inside the CellA Complex Network of Protein Interactions Underlies Cell FunctionSummaryProblemsReferences155156157157158159160161163164164165166169170172Chapter 4 DNA, Chromosomes, and Genomes173THE STRUCTURE AND FUNCTION OF DNAA DNA Molecule Consists of Two Complementary Chains ofNucleotidesThe Structure of DNA Provides a Mechanism for HeredityIn Eukaryotes, DNA Is Enclosed in a Cell NucleusSummary173CHROMOSOMAL DNA AND ITS PACKAGING IN THECHROMATIN FIBEREukaryotic DNA Is Packaged into a Set of ChromosomesChromosomes Contain Long Strings of GenesThe Nucleotide Sequence of the Human Genome Shows HowOur Genes Are ArrangedEach DNA Molecule That Forms a Linear Chromosome MustContain a Centromere, Two Telomeres, and ReplicationOriginsDNA Molecules Are Highly Condensed in ChromosomesNucleosomes Are a Basic Unit of Eukaryotic ChromosomeStructureThe Structure of the Nucleosome Core Particle Reveals HowDNA Is PackagedNucleosomes Have a Dynamic Structure, and Are FrequentlySubjected to Changes Catalyzed by ATP-DependentChromatin Remodeling ComplexesNucleosomes Are Usually Packed Together into a CompactChromatin FiberSummaryCHROMATIN STRUCTURE AND FUNCTIONHeterochromatin Is Highly Organized and Restricts GeneExpressionThe Heterochromatic State Is Self-PropagatingThe Core Histones Are Covalently Modified at Many Different SitesChromatin Acquires Additional Variety Through the Site-SpecificInsertion of a Small Set of Histone VariantsCovalent Modifications and Histone Variants Act in Concert toControl Chromosome FunctionsA Complex of Reader and Writer Proteins Can Spread SpecificChromatin Modifications Along a ChromosomeBarrier DNA Sequences Block the Spread of Reader–WriterComplexes and thereby Separate Neighboring ChromatinDomainsThe Chromatin in Centromeres Reveals How Histone VariantsCan Create Special StructuresSome Chromatin Structures Can Be Directly Inherited175177178179179180182183185187187188190191193194194194196198198199202203204DETAILED CONTENTSExperiments with Frog Embryos Suggest that both Activatingand Repressive Chromatin Structures Can Be InheritedEpigeneticallyChromatin Structures Are Important for Eukaryotic ChromosomeFunctionSummaryTHE GLOBAL STRUCTURE OF CHROMOSOMESChromosomes Are Folded into Large Loops of ChromatinPolytene Chromosomes Are Uniquely Useful for VisualizingChromatin StructuresThere Are Multiple Forms of ChromatinChromatin Loops Decondense When the Genes Within ThemAre ExpressedChromatin Can Move to Specific Sites Within the Nucleus toAlter Gene ExpressionNetworks of Macromolecules Form a Set of Distinct BiochemicalEnvironments inside the NucleusMitotic Chromosomes Are Especially Highly CondensedSummaryHOW GENOMES EVOLVEGenome Comparisons Reveal Functional DNA Sequences bytheir Conservation Throughout EvolutionGenome Alterations Are Caused by Failures of the NormalMechanisms for Copying and Maintaining DNA, as well asby Transposable DNA ElementsThe Genome Sequences of Two Species Differ in Proportion tothe Length of Time Since They Have Separately EvolvedPhylogenetic Trees Constructed from a Comparison of DNASequences Trace the Relationships of All OrganismsA Comparison of Human and Mouse Chromosomes ShowsHow the Structures of Genomes DivergeThe Size of a Vertebrate Genome Reflects the Relative Ratesof DNA Addition and DNA Loss in a LineageWe Can Infer the Sequence of Some Ancient GenomesMultispecies Sequence Comparisons Identify Conserved DNASequences of Unknown FunctionChanges in Previously Conserved Sequences Can HelpDecipher Critical Steps in EvolutionMutations in the DNA Sequences That Control Gene ExpressionHave Driven Many of the Evolutionary Changes in VertebratesGene Duplication Also Provides an Important Source of GeneticNovelty During EvolutionDuplicated Genes DivergeThe Evolution of the Globin Gene Family Shows How DNADuplications Contribute to the Evolution of OrganismsGenes Encoding New Proteins Can Be Created by theRecombination of ExonsNeutral Mutations Often Spread to Become Fixed in a Population,with a Probability That Depends on Population SizeA Great Deal Can Be Learned from Analyses of the VariationAmong HumansSummaryProblemsReferencesChapter 5 DNA Replication, Repair, andRecombinationTHE MAINTENANCE OF DNA SEQUENCESMutation Rates Are Extremely LowLow Mutation Rates Are Necessary for Life as We Know ItSummaryDNA REPLICATION MECHANISMSBase-Pairing Underlies DNA Replication and DNA RepairThe DNA Replication Fork Is AsymmetricalThe High Fidelity of DNA Replication Requires SeveralProofreading MechanismsOnly DNA Replication in the 5ʹ-to-3ʹ Direction Allows EfficientError CorrectionA Special Nucleotide-Polymerizing Enzyme Synthesizes ShortRNA Primer Molecules on the Lagging StrandSpecial Proteins Help to Open Up the DNA Double Helix in Frontof the Replication ForkA Sliding Ring Holds a Moving DNA Polymerase Onto the DNAxxiii205206207207207208210211212213214216216217217218219221222223224226227227228229230230232234234236237237237238239239239240242244245246246The Proteins at a Replication Fork Cooperate to Form aReplication MachineA Strand-Directed Mismatch Repair System Removes ReplicationErrors That Escape from the Replication MachineDNA Topoisomerases Prevent DNA Tangling During ReplicationDNA Replication Is Fundamentally Similar in Eukaryotes andBacteriaSummaryTHE INITIATION AND COMPLETION OF DNA REPLICATIONIN CHROMOSOMESDNA Synthesis Begins at Replication OriginsBacterial Chromosomes Typically Have a Single Origin of DNAReplicationEukaryotic Chromosomes Contain Multiple Origins of ReplicationIn Eukaryotes, DNA Replication Takes Place During Only OnePart of the Cell CycleDifferent Regions on the Same Chromosome Replicate at DistinctTimes in S PhaseA Large Multisubunit Complex Binds to Eukaryotic Origins ofReplicationFeatures of the Human Genome That Specify Origins ofReplication Remain to Be DiscoveredNew Nucleosomes Are Assembled Behind the Replication ForkTelomerase Replicates the Ends of ChromosomesTelomeres Are Packaged Into Specialized Structures ThatProtect the Ends of ChromosomesTelomere Length Is Regulated by Cells and OrganismsSummaryDNA REPAIRWithout DNA Repair, Spontaneous DNA Damage Would RapidlyChange DNA SequencesThe DNA Double Helix Is Readily RepairedDNA Damage Can Be Removed by More Than One PathwayCoupling Nucleotide Excision Repair to Transcription EnsuresThat the Cell’s Most Important DNA Is Efficiently RepairedThe Chemistry of the DNA Bases Facilitates Damage DetectionSpecial Translesion DNA Polymerases Are Used in EmergenciesDouble-Strand Breaks Are Efficiently RepairedDNA Damage Delays Progression of the Cell CycleSummaryHOMOLOGOUS RECOMBINATIONHomologous Recombination Has Common Features in All CellsDNA Base-Pairing Guides Homologous RecombinationHomologous Recombination Can Flawlessly Repair DoubleStrand Breaks in DNAStrand Exchange Is Carried Out by the RecA/Rad51 ProteinHomologous Recombination Can Rescue Broken DNAReplication ForksCells Carefully Regulate the Use of Homologous Recombinationin DNA RepairHomologous Recombination Is Crucial for MeiosisMeiotic Recombination Begins with a Programmed Double-StrandBreakHolliday Junctions Are Formed During MeiosisHomologous Recombination Produces Both Crossovers andNon-Crossovers During MeiosisHomologous Recombination Often Results in Gene ConversionSummaryTRANSPOSITION AND CONSERVATIVE SITE-SPECIFICRECOMBINATIONThrough Transposition, Mobile Genetic Elements Can InsertInto Any DNA SequenceDNA-Only Transposons Can Move by a Cut-and-PasteMechanismSome Viruses Use a Transposition Mechanism to MoveThemselves Into Host-Cell ChromosomesRetroviral-like Retrotransposons Resemble Retroviruses, butLack a Protein CoatA Large Fraction of the Human Genome Is Composed ofNonretroviral RetrotransposonsDifferent Transposable Elements Predominate in DifferentOrganismsGenome Sequences Reveal the Approximate Times at WhichTransposable Elements Have Moved249250251253254254254255256258258259260261262263264265266267268269271271273273276276276277277278279280280282282284284286286287288288290291291292292xxivDETAILED CONTENTSConservative Site-Specific Recombination Can ReversiblyRearrange DNAConservative Site-Specific Recombination Can Be Used toTurn Genes On or OffBacterial Conservative Site-Specific Recombinases Have BecomePowerful Tools for Cell and Developmental BiologistsSummaryProblemsReferencesChapter 6 How Cells Read the Genome:From DNA to ProteinFROM DNA TO RNARNA Molecules Are Single-StrandedTranscription Produces RNA Complementary to One Strandof DNARNA Polymerases Carry Out TranscriptionCells Produce Different Categories of RNA MoleculesSignals Encoded in DNA Tell RNA Polymerase Where to Startand StopTranscription Start and Stop Signals Are Heterogeneous inNucleotide SequenceTranscription Initiation in Eukaryotes Requires Many ProteinsRNA Polymerase II Requires a Set of General TranscriptionFactorsPolymerase II Also Requires Activator, Mediator, and ChromatinModifying ProteinsTranscription Elongation in Eukaryotes Requires AccessoryProteinsTranscription Creates Superhelical TensionTranscription Elongation in Eukaryotes Is Tightly Coupled to RNAProcessingRNA Capping Is the First Modification of Eukaryotic Pre-mRNAsRNA Splicing Removes Intron Sequences from NewlyTranscribed Pre-mRNAsNucleotide Sequences Signal Where Splicing OccursRNA Splicing Is Performed by the SpliceosomeThe Spliceosome Uses ATP Hydrolysis to Produce a ComplexSeries of RNA–RNA RearrangementsOther Properties of Pre-mRNA and Its Synthesis Help to Explainthe Choice of Proper Splice SitesChromatin Structure Affects RNA SplicingRNA Splicing Shows Remarkable PlasticitySpliceosome-Catalyzed RNA Splicing Probably Evolved fromSelf-splicing MechanismsRNA-Processing Enzymes Generate the 3ʹ End of EukaryoticmRNAsMature Eukaryotic mRNAs Are Selectively Exported from theNucleusNoncoding RNAs Are Also Synthesized and Processed in theNucleusThe Nucleolus Is a Ribosome-Producing FactoryThe Nucleus Contains a Variety of Subnuclear AggregatesSummaryFROM RNA TO PROTEINAn mRNA Sequence Is Decoded in Sets of Three NucleotidestRNA Molecules Match Amino Acids to Codons in mRNAtRNAs Are Covalently Modified Before They Exit from the NucleusSpecific Enzymes Couple Each Amino Acid to Its AppropriatetRNA MoleculeEditing by tRNA Synthetases Ensures AccuracyAmino Acids Are Added to the C-terminal End of a GrowingPolypeptide ChainThe RNA Message Is Decoded in RibosomesElongation Factors Drive Translation Forward and Improve ItsAccuracyMany Biological Processes Overcome the Inherent Limitations ofComplementary Base-PairingAccuracy in Translation Requires an Expenditure of Free EnergyThe Ribosome Is a RibozymeNucleotide Sequences in mRNA Signal Where to Start ProteinSynthesisStop Codons Mark the End of Translation292294294295296298299301302302303305306307309310Proteins Are Made on PolyribosomesThere Are Minor Variations in the Standard Genetic CodeInhibitors of Prokaryotic Protein Synthesis Are Useful asAntibioticsQuality Control Mechanisms Act to Prevent Translation ofDamaged mRNAsSome Proteins Begin to Fold While Still Being SynthesizedMolecular Chaperones Help Guide the Folding of Most ProteinsCells Utilize Several Types of ChaperonesExposed Hydrophobic Regions Provide Critical Signals forProtein Quality ControlThe Proteasome Is a Compartmentalized Protease withSequestered Active SitesMany Proteins Are Controlled by Regulated DestructionThere Are Many Steps From DNA to ProteinSummaryTHE RNA WORLD AND THE ORIGINS OF LIFESingle-Stranded RNA Molecules Can Fold into Highly ElaborateStructuresRNA Can Both Store Information and Catalyze ChemicalReactionsHow Did Protein Synthesis Evolve?All Present-Day Cells Use DNA as Their Hereditary MaterialSummaryProblemsReferences312Chapter 7 Control of Gene Expression313314AN OVERVIEW OF GENE CONTROLThe Different Cell Types of a Multicellular Organism Containthe Same DNADifferent Cell Types Synthesize Different Sets of RNAs andProteinsExternal Signals Can Cause a Cell to Change the Expressionof Its GenesGene Expression Can Be Regulated at Many of the Stepsin the Pathway from DNA to RNA to ProteinSummary315316317319319321321323323324324325327329331333333334334336336338339340343345345346347348CONTROL OF TRANSCRIPTION BY SEQUENCE-SPECIFICDNA-BINDING PROTEINSThe Sequence of Nucleotides in the DNA Double Helix Can BeRead by ProteinsTranscription Regulators Contain Structural Motifs That CanRead DNA SequencesDimerization of Transcription Regulators Increases Their Affinityand Specificity for DNATranscription Regulators Bind Cooperatively to DNANucleosome Structure Promotes Cooperative Binding ofTranscription RegulatorsSummaryTRANSCRIPTION REGULATORS SWITCH GENES ONAND OFFThe Tryptophan Repressor Switches Genes OffRepressors Turn Genes Off and Activators Turn Them OnAn Activator and a Repressor Control the Lac OperonDNA Looping Can Occur During Bacterial Gene RegulationComplex Switches Control Gene Transcription in EukaryotesA Eukaryotic Gene Control Region Consists of a PromoterPlus Many cis-Regulatory SequencesEukaryotic Transcription Regulators Work in GroupsActivator Proteins Promote the Assembly of RNA Polymeraseat the Start Point of TranscriptionEukaryotic Transcription Activators Direct the Modification ofLocal Chromatin StructureTranscription Activators Can Promote Transcription by ReleasingRNA Polymerase from PromotersTranscription Activators Work SynergisticallyEukaryotic Transcription Repressors Can Inhibit Transcriptionin Several WaysInsulator DNA Sequences Prevent Eukaryotic TranscriptionRegulators from Influencing Distant GenesSummary349349351351353354355357357359361362362363364365365366366368369369369370372372373373373374375378379380380380381382383384384385386386388388389391392DETAILED CONTENTSMOLECULAR GENETIC MECHANISMS THAT CREATE ANDMAINTAIN SPECIALIZED CELL TYPESComplex Genetic Switches That Regulate DrosophilaDevelopment Are Built Up from Smaller MoleculesThe Drosophila Eve Gene Is Regulated by Combinatorial ControlsTranscription Regulators Are Brought Into Play by ExtracellularSignalsCombinatorial Gene Control Creates Many Different Cell TypesSpecialized Cell Types Can Be Experimentally Reprogrammedto Become Pluripotent Stem CellsCombinations of Master Transcription Regulators Specify CellTypes by Controlling the Expression of Many GenesSpecialized Cells Must Rapidly Turn Sets of Genes On and OffDifferentiated Cells Maintain Their IdentityTranscription Circuits Allow the Cell to Carry Out Logic OperationsSummaryMECHANISMS THAT REINFORCE CELL MEMORY INPLANTS AND ANIMALSPatterns of DNA Methylation Can Be Inherited When VertebrateCells DivideCG-Rich Islands Are Associated with Many Genes in MammalsGenomic Imprinting Is Based on DNA MethylationChromosome-Wide Alterations in Chromatin Structure Can BeInheritedEpigenetic Mechanisms Ensure That Stable Patterns of GeneExpression Can Be Transmitted to Daughter CellsSummaryPOST-TRANSCRIPTIONAL CONTROLSTranscription Attenuation Causes the Premature Termination ofSome RNA MoleculesRiboswitches Probably Represent Ancient Forms of Gene ControlAlternative RNA Splicing Can Produce Different Forms of a Proteinfrom the Same GeneThe Definition of a Gene Has Been Modified Since the Discoveryof Alternative RNA SplicingA Change in the Site of RNA Transcript Cleavage and Poly-AAddition Can Change the C-terminus of a ProteinRNA Editing Can Change the Meaning of the RNA MessageRNA Transport from the Nucleus Can Be RegulatedSome mRNAs Are Localized to Specific Regions of the CytosolThe 5ʹ and 3ʹ Untranslated Regions of mRNAs Control TheirTranslationThe Phosphorylation of an Initiation Factor Regulates ProteinSynthesis GloballyInitiation at AUG Codons Upstream of the Translation Start CanRegulate Eukaryotic Translation InitiationInternal Ribosome Entry Sites Provide Opportunities forTranslational ControlChanges in mRNA Stability Can Regulate Gene ExpressionRegulation of mRNA Stability Involves P-bodies and StressGranulesSummaryREGULATION OF GENE EXPRESSION BY NONCODING RNAsSmall Noncoding RNA Transcripts Regulate Many Animal andPlant Genes Through RNA InterferencemiRNAs Regulate mRNA Translation and StabilityRNA Interference Is Also Used as a Cell Defense MechanismRNA Interference Can Direct Heterochromatin FormationpiRNAs Protect the Germ Line from Transposable ElementsRNA Interference Has Become a Powerful Experimental ToolBacteria Use Small Noncoding RNAs to Protect Themselvesfrom VirusesLong Noncoding RNAs Have Diverse Functions in the CellSummaryProblemsReferencesChapter 8 Analyzing Cells, Molecules, andSystemsISOLATING CELLS AND GROWING THEM IN CULTURECells Can Be Isolated from TissuesCells Can Be Grown in CultureEukaryotic Cell Lines Are a Widely Used Source ofHomogeneous Cellsxxv392392394395396398398399400402404404404405407409411413413414414415416417418419421422423424425426427428429429429431432433433433435436436438439440440440442Hybridoma Cell Lines Are Factories That Produce MonoclonalAntibodiesSummaryPURIFYING PROTEINSCells Can Be Separated into Their Component FractionsCell Extracts Provide Accessible Systems to Study Cell FunctionsProteins Can Be Separated by ChromatographyImmunoprecipitation Is a Rapid Affinity Purification MethodGenetically Engineered Tags Provide an Easy Way to PurifyProteinsPurified Cell-free Systems Are Required for the PreciseDissection of Molecular FunctionsSummaryANALYZING PROTEINSProteins Can Be Separated by SDS Polyacrylamide-GelElectrophoresisTwo-Dimensional Gel Electrophoresis Provides Greater ProteinSeparationSpecific Proteins Can Be Detected by Blotting with AntibodiesHydrodynamic Measurements Reveal the Size and Shape ofa Protein ComplexMass Spectrometry Provides a Highly Sensitive Method forIdentifying Unknown ProteinsSets of Interacting Proteins Can Be Identified by BiochemicalMethodsOptical Methods Can Monitor Protein InteractionsProtein Function Can Be Selectively Disrupted With SmallMoleculesProtein Structure Can Be Determined Using X-Ray DiffractionNMR Can Be Used to Determine Protein Structure in SolutionProtein Sequence and Structure Provide Clues About ProteinFunctionSummaryANALYZING AND MANIPULATING DNARestriction Nucleases Cut Large DNA Molecules into SpecificFragmentsGel Electrophoresis Separates DNA Molecules of Different SizesPurified DNA Molecules Can Be Specifically Labeled withRadioisotopes or Chemical Markers in vitroGenes Can Be Cloned Using BacteriaAn Entire Genome Can Be Represented in a DNA LibraryGenomic and cDNA Libraries Have Different Advantages andDrawbacksHybridization Provides a Powerful, But Simple Way to DetectSpecific Nucleotide SequencesGenes Can Be Cloned in vitro Using PCRPCR Is Also Used for Diagnostic and Forensic ApplicationsBoth DNA and RNA Can Be Rapidly SequencedTo Be Useful, Genome Sequences Must Be AnnotatedDNA Cloning Allows Any Protein to be Produced in LargeAmountsSummarySTUDYING GENE EXPRESSION AND FUNCTIONClassical Genetics Begins by Disrupting a Cell Process byRandom MutagenesisGenetic Screens Identify Mutants with Specific AbnormalitiesMutations Can Cause Loss or Gain of Protein FunctionComplementation Tests Reveal Whether Two Mutations Are in theSame Gene or Different GenesGene Products Can Be Ordered in Pathways by EpistasisAnalysisMutations Responsible for a Phenotype Can Be IdentifiedThrough DNA AnalysisRapid and Cheap DNA Sequencing Has RevolutionizedHuman Genetic StudiesLinked Blocks of Polymorphisms Have Been Passed Downfrom Our AncestorsPolymorphisms Can Aid the Search for Mutations Associatedwith DiseaseGenomics Is Accelerating the Discovery of Rare Mutations ThatPredispose Us to Serious DiseaseReverse Genetics Begins with a Known Gene and DeterminesWhich Cell Processes Require Its FunctionAnimals and Plants Can Be Genetically Altered444445445445447448449450451451452452452454455455457458459460461462463463464465467467469471472473474477477483484485485488489490490491491492493493494495xxviDETAILED CONTENTSThe Bacterial CRISPR System Has Been Adapted to EditGenomes in a Wide Variety of SpeciesLarge Collections of Engineered Mutations Provide a Tool forExamining the Function of Every Gene in an OrganismRNA Interference Is a Simple and Rapid Way to Test GeneFunctionReporter Genes Reveal When and Where a Gene Is ExpressedIn situ Hybridization Can Reveal the Location of mRNAs andNoncoding RNAsExpression of Individual Genes Can Be Measured UsingQuantitative RT-PCRAnalysis of mRNAs by Microarray or RNA-seq Provides aSnapshot of Gene ExpressionGenome-wide Chromatin Immunoprecipitation Identifies Siteson the Genome Occupied by Transcription RegulatorsRibosome Profiling Reveals Which mRNAs Are Being Translatedin the CellRecombinant DNA Methods Have Revolutionized Human HealthTransgenic Plants Are Important for AgricultureSummaryMATHEMATICAL ANALYSIS OF CELL FUNCTIONSRegulatory Networks Depend on Molecular InteractionsDifferential Equations Help Us Predict Transient BehaviorBoth Promoter Activity and Protein Degradation Affect the Rateof Change of Protein ConcentrationThe Time Required to Reach Steady State Depends on ProteinLifetimeQuantitative Methods Are Similar for Transcription Repressorsand ActivatorsNegative Feedback Is a Powerful Strategy in Cell RegulationDelayed Negative Feedback Can Induce OscillationsDNA Binding By a Repressor or an Activator Can Be CooperativePositive Feedback Is Important for Switchlike Responsesand BistabilityRobustness Is an Important Characteristic of Biological NetworksTwo Transcription Regulators That Bind to the Same GenePromoter Can Exert Combinatorial ControlAn Incoherent Feed-forward Interaction Generates PulsesA Coherent Feed-forward Interaction Detects Persistent InputsThe Same Network Can Behave Differently in Different Cells Dueto Stochastic EffectsSeveral Computational Approaches Can Be Used to Model theReactions in CellsStatistical Methods Are Critical For the Analysis of Biological DataSummaryProblemsReferencesChapter 9 Visualizing CellsLOOKING AT CELLS IN THE LIGHT MICROSCOPEThe Light Microscope Can Resolve Details 0.2 μm ApartPhoton Noise Creates Additional Limits to Resolution WhenLight Levels Are LowLiving Cells Are Seen Clearly in a Phase-Contrast or aDifferential-Interference-Contrast MicroscopeImages Can Be Enhanced and Analyzed by Digital TechniquesIntact Tissues Are Usually Fixed and Sectioned Before MicroscopySpecific Molecules Can Be Located in Cells by FluorescenceMicroscopyAntibodies Can Be Used to Detect Specific MoleculesImaging of Complex Three-Dimensional Objects Is Possible withthe Optical MicroscopeThe Confocal Microscope Produces Optical Sections byExcluding Out-of-Focus LightIndividual Proteins Can Be Fluorescently Tagged in Living Cellsand OrganismsProtein Dynamics Can Be Followed in Living CellsLight-Emitting Indicators Can Measure Rapidly ChangingIntracellular Ion ConcentrationsSingle Molecules Can Be Visualized by Total Internal ReflectionFluorescence MicroscopyIndividual Molecules Can Be Touched, Imaged, and Moved UsingAtomic Force Microscopy497498499501502502503505505506507508509509512513514514515516516518520520522522523524524525525528529529530532533534535536539540540542543546547548Superresolution Fluorescence Techniques Can OvercomeDiffraction-Limited ResolutionSuperresolution Can Also be Achieved Using Single-MoleculeLocalization MethodsSummaryLOOKING AT CELLS AND MOLECULES IN THE ELECTRONMICROSCOPEThe Electron Microscope Resolves the Fine Structure of the CellBiological Specimens Require Special Preparation for ElectronMicroscopySpecific Macromolecules Can Be Localized by ImmunogoldElectron MicroscopyDifferent Views of a Single Object Can Be Combined to Givea Three-Dimensional ReconstructionImages of Surfaces Can Be Obtained by Scanning ElectronMicroscopyNegative Staining and Cryoelectron Microscopy Both AllowMacromolecules to Be Viewed at High ResolutionMultiple Images Can Be Combined to Increase ResolutionSummaryProblemsReferencesChapter 10 Membrane StructureTHE LIPID BILAYERPhosphoglycerides, Sphingolipids, and Sterols Are the MajorLipids in Cell MembranesPhospholipids Spontaneously Form BilayersThe Lipid Bilayer Is a Two-dimensional FluidThe Fluidity of a Lipid Bilayer Depends on Its CompositionDespite Their Fluidity, Lipid Bilayers Can Form Domains ofDifferent CompositionsLipid Droplets Are Surrounded by a Phospholipid MonolayerThe Asymmetry of the Lipid Bilayer Is Functionally ImportantGlycolipids Are Found on the Surface of All Eukaryotic PlasmaMembranesSummaryMEMBRANE PROTEINSMembrane Proteins Can Be Associated with the Lipid Bilayerin Various WaysLipid Anchors Control the Membrane Localization of SomeSignaling ProteinsIn Most Transmembrane Proteins, the Polypeptide ChainCrosses the Lipid Bilayer in an α-Helical ConformationTransmembrane α Helices Often Interact with One AnotherSome β Barrels Form Large ChannelsMany Membrane Proteins Are GlycosylatedMembrane Proteins Can Be Solubilized and Purified in DetergentsBacteriorhodopsin Is a Light-driven Proton (H+) Pump ThatTraverses the Lipid Bilayer as Seven α HelicesMembrane Proteins Often Function as Large ComplexesMany Membrane Proteins Diffuse in the Plane of the MembraneCells Can Confine Proteins and Lipids to Specific DomainsWithin a MembraneThe Cortical Cytoskeleton Gives Membranes MechanicalStrength and Restricts Membrane Protein DiffusionMembrane-bending Proteins Deform BilayersSummaryProblemsReferences549551554554554555556557558559561562563564565566566568569571572573573575576576576577579580580582583586588588590591593594595596Chapter 11 Membrane Transport of Small Moleculesand the Electrical Properties of Membranes597PRINCIPLES OF MEMBRANE TRANSPORTProtein-Free Lipid Bilayers Are Impermeable to IonsThere Are Two Main Classes of Membrane Transport Proteins:Transporters and ChannelsActive Transport Is Mediated by Transporters Coupled to anEnergy SourceSummaryTRANSPORTERS AND ACTIVE MEMBRANE TRANSPORTActive Transport Can Be Driven by Ion-Concentration Gradients597598598599600600601DETAILED CONTENTSTransporters in the Plasma Membrane Regulate Cytosolic pHAn Asymmetric Distribution of Transporters in Epithelial CellsUnderlies the Transcellular Transport of SolutesThere Are Three Classes of ATP-Driven PumpsA P-type ATPase Pumps Ca2+ into the Sarcoplasmic Reticulumin Muscle CellsThe Plasma Membrane Na+-K+ Pump Establishes Na+ and K+Gradients Across the Plasma MembraneABC Transporters Constitute the Largest Family of MembraneTransport ProteinsSummaryCHANNELS AND THE ELECTRICAL PROPERTIES OFMEMBRANESAquaporins Are Permeable to Water But Impermeable to IonsIon Channels Are Ion-Selective and Fluctuate Between Openand Closed StatesThe Membrane Potential in Animal Cells Depends Mainly on K+Leak Channels and the K+ Gradient Across the PlasmaMembraneThe Resting Potential Decays Only Slowly When the Na+-K+Pump Is StoppedThe Three-Dimensional Structure of a Bacterial K+ ChannelShows How an Ion Channel Can WorkMechanosensitive Channels Protect Bacterial Cells AgainstExtreme Osmotic PressuresThe Function of a Neuron Depends on Its Elongated StructureVoltage-Gated Cation Channels Generate Action Potentials inElectrically Excitable CellsThe Use of Channelrhodopsins Has Revolutionized the Studyof Neural CircuitsMyelination Increases the Speed and Efficiency of Action PotentialPropagation in Nerve CellsPatch-Clamp Recording Indicates That Individual Ion ChannelsOpen in an All-or-Nothing FashionVoltage-Gated Cation Channels Are Evolutionarily and StructurallyRelatedDifferent Neuron Types Display Characteristic Stable FiringPropertiesTransmitter-Gated Ion Channels Convert Chemical Signals intoElectrical Ones at Chemical SynapsesChemical Synapses Can Be Excitatory or InhibitoryThe Acetylcholine Receptors at the Neuromuscular Junction AreExcitatory Transmitter-Gated Cation ChannelsNeurons Contain Many Types of Transmitter-Gated ChannelsMany Psychoactive Drugs Act at SynapsesNeuromuscular Transmission Involves the Sequential Activationof Five Different Sets of Ion ChannelsSingle Neurons Are Complex Computation DevicesNeuronal Computation Requires a Combination of at Least ThreeKinds of K+ ChannelsLong-Term Potentiation (LTP) in the Mammalian HippocampusDepends on Ca2+ Entry Through NMDA-Receptor ChannelsSummaryProblemsReferencesChapter 12 Intracellular Compartments andProtein SortingTHE COMPARTMENTALIZATION OF CELLSAll Eukaryotic Cells Have the Same Basic Set of Membraneenclosed OrganellesEvolutionary Origins May Help Explain the TopologicalRelationships of OrganellesProteins Can Move Between Compartments in Different WaysSignal Sequences and Sorting Receptors Direct Proteins to theCorrect Cell AddressMost Organelles Cannot Be Constructed De Novo: They RequireInformation in the Organelle ItselfSummaryTHE TRANSPORT OF MOLECULES BETWEEN THENUCLEUS AND THE CYTOSOLNuclear Pore Complexes Perforate the Nuclear EnvelopeNuclear Localization Signals Direct Nuclear Proteins to the Nucleusxxvii604605606606607609611611612613615615617619620621623625626626627627629630631631632633634636637638640641641641643645647648649649649650Nuclear Import Receptors Bind to Both Nuclear LocalizationSignals and NPC ProteinsNuclear Export Works Like Nuclear Import, But in ReverseThe Ran GTPase Imposes Directionality on Transport ThroughNPCsTransport Through NPCs Can Be Regulated by ControllingAccess to the Transport MachineryDuring Mitosis the Nuclear Envelope DisassemblesSummaryTHE TRANSPORT OF PROTEINS INTO MITOCHONDRIA ANDCHLOROPLASTSTranslocation into Mitochondria Depends on Signal Sequencesand Protein TranslocatorsMitochondrial Precursor Proteins Are Imported as UnfoldedPolypeptide ChainsATP Hydrolysis and a Membrane Potential Drive Protein ImportInto the Matrix SpaceBacteria and Mitochondria Use Similar Mechanisms to InsertPorins into their Outer MembraneTransport Into the Inner Mitochondrial Membrane andIntermembrane Space Occurs Via Several RoutesTwo Signal Sequences Direct Proteins to the Thylakoid Membranein ChloroplastsSummary652652653654656657658659660661662663664666PEROXISOMESPeroxisomes Use Molecular Oxygen and Hydrogen Peroxideto Perform Oxidation ReactionsA Short Signal Sequence Directs the Import of Proteins intoPeroxisomesSummary666THE ENDOPLASMIC RETICULUMThe ER Is Structurally and Functionally DiverseSignal Sequences Were First Discovered in Proteins Importedinto the Rough ERA Signal-Recognition Particle (SRP) Directs the ER SignalSequence to a Specific Receptor in the Rough ER MembraneThe Polypeptide Chain Passes Through an Aqueous Channelin the TranslocatorTranslocation Across the ER Membrane Does Not AlwaysRequire Ongoing Polypeptide Chain ElongationIn Single-Pass Transmembrane Proteins, a Single Internal ERSignal Sequence Remains in the Lipid Bilayer as a Membranespanning α HelixCombinations of Start-Transfer and Stop-Transfer SignalsDetermine the Topology of Multipass Transmembrane ProteinsER Tail-anchored Proteins Are Integrated into the ER Membraneby a Special MechanismTranslocated Polypeptide Chains Fold and Assemble in theLumen of the Rough ERMost Proteins Synthesized in the Rough ER Are Glycosylated bythe Addition of a Common N-Linked OligosaccharideOligosaccharides Are Used as Tags to Mark the State of ProteinFoldingImproperly Folded Proteins Are Exported from the ER andDegraded in the CytosolMisfolded Proteins in the ER Activate an Unfolded ProteinResponseSome Membrane Proteins Acquire a Covalently AttachedGlycosylphosphatidylinositol (GPI) AnchorThe ER Assembles Most Lipid BilayersSummaryProblemsReferences669670Chapter 13 Intracellular Membrane TrafficTHE MOLECULAR MECHANISMS OF MEMBRANETRANSPORT AND THE MAINTENANCE OFCOMPARTMENTAL DIVERSITYThere Are Various Types of Coated VesiclesThe Assembly of a Clathrin Coat Drives Vesicle FormationAdaptor Proteins Select Cargo into Clathrin-Coated VesiclesPhosphoinositides Mark Organelles and Membrane Domains666667669672673675677677679682682683685685686688689691692694695697697697698700xxviiiDETAILED CONTENTSMembrane-Bending Proteins Help Deform the Membrane DuringVesicle FormationCytoplasmic Proteins Regulate the Pinching-Off and Uncoatingof Coated VesiclesMonomeric GTPases Control Coat AssemblyNot All Transport Vesicles Are SphericalRab Proteins Guide Transport Vesicles to Their Target MembraneRab Cascades Can Change the Identity of an OrganelleSNAREs Mediate Membrane FusionInteracting SNAREs Need to Be Pried Apart Before They CanFunction AgainSummaryTRANSPORT FROM THE ER THROUGH THE GOLGIAPPARATUSProteins Leave the ER in COPII-Coated Transport VesiclesOnly Proteins That Are Properly Folded and Assembled CanLeave the ERVesicular Tubular Clusters Mediate Transport from the ER tothe Golgi ApparatusThe Retrieval Pathway to the ER Uses Sorting SignalsMany Proteins Are Selectively Retained in the Compartmentsin Which They FunctionThe Golgi Apparatus Consists of an Ordered Series ofCompartmentsOligosaccharide Chains Are Processed in the Golgi ApparatusProteoglycans Are Assembled in the Golgi ApparatusWhat Is the Purpose of Glycosylation?Transport Through the Golgi Apparatus May Occur byCisternal MaturationGolgi Matrix Proteins Help Organize the StackSummaryTRANSPORT FROM THE TRANS GOLGI NETWORK TOLYSOSOMESLysosomes Are the Principal Sites of Intracellular DigestionLysosomes Are HeterogeneousPlant and Fungal Vacuoles Are Remarkably Versatile LysosomesMultiple Pathways Deliver Materials to LysosomesAutophagy Degrades Unwanted Proteins and OrganellesA Mannose 6-Phosphate Receptor Sorts Lysosomal Hydrolasesin the Trans Golgi NetworkDefects in the GlcNAc Phosphotransferase Cause a LysosomalStorage Disease in HumansSome Lysosomes and Multivesicular Bodies UndergoExocytosisSummaryTRANSPORT INTO THE CELL FROM THE PLASMAMEMBRANE: ENDOCYTOSISPinocytic Vesicles Form from Coated Pits in the PlasmaMembraneNot All Pinocytic Vesicles Are Clathrin-CoatedCells Use Receptor-Mediated Endocytosis to Import SelectedExtracellular MacromoleculesSpecific Proteins Are Retrieved from Early Endosomes andReturned to the Plasma MembranePlasma Membrane Signaling Receptors are Down-Regulatedby Degradation in LysosomesEarly Endosomes Mature into Late EndosomesESCRT Protein Complexes Mediate the Formation ofIntralumenal Vesicles in Multivesicular BodiesRecycling Endosomes Regulate Plasma Membrane CompositionSpecialized Phagocytic Cells Can Ingest Large ParticlesSummaryTRANSPORT FROM THE TRANS GOLGI NETWORK TOTHE CELL EXTERIOR: EXOCYTOSISMany Proteins and Lipids Are Carried Automatically from theTrans Golgi Network (TGN) to the Cell SurfaceSecretory Vesicles Bud from the Trans Golgi NetworkPrecursors of Secretory Proteins Are Proteolytically ProcessedDuring the Formation of Secretory VesiclesSecretory Vesicles Wait Near the Plasma Membrane UntilSignaled to Release Their ContentsFor Rapid Exocytosis, Synaptic Vesicles Are Primed at thePresynaptic Plasma MembraneSynaptic Vesicles Can Form Directly from Endocytic Vesicles701701703704705707708Secretory Vesicle Membrane Components Are Quickly Removedfrom the Plasma MembraneSome Regulated Exocytosis Events Serve to Enlarge the PlasmaMembranePolarized Cells Direct Proteins from the Trans Golgi Networkto the Appropriate Domain of the Plasma MembraneSummaryProblemsReferences709710Chapter 14 Energy Conversion: Mitochondriaand Chloroplasts710711THE MITOCHONDRIONThe Mitochondrion Has an Outer Membrane and an InnerMembraneThe Inner Membrane Cristae Contain the Machinery for ElectronTransport and ATP SynthesisThe Citric Acid Cycle in the Matrix Produces NADHMitochondria Have Many Essential Roles in Cellular MetabolismA Chemiosmotic Process Couples Oxidation Energy to ATPProductionThe Energy Derived from Oxidation Is Stored as anElectrochemical GradientSummaryTHE PROTON PUMPS OF THE ELECTRON-TRANSPORTCHAINThe Redox Potential Is a Measure of Electron AffinitiesElectron Transfers Release Large Amounts of EnergyTransition Metal Ions and Quinones Accept and ReleaseElectrons ReadilyNADH Transfers Its Electrons to Oxygen Through ThreeLarge Enzyme Complexes Embedded in the InnerMembraneThe NADH Dehydrogenase Complex Contains SeparateModules for Electron Transport and Proton PumpingCytochrome c Reductase Takes Up and Releases Protons onthe Opposite Side of the Crista Membrane, TherebyPumping ProtonsThe Cytochrome c Oxidase Complex Pumps Protons andReduces O2 Using a Catalytic Iron–Copper CenterThe Respiratory Chain Forms a Supercomplex in the CristaMembraneProtons Can Move Rapidly Through Proteins Along PredefinedPathwaysSummaryATP PRODUCTION IN MITOCHONDRIAThe Large Negative Value of ∆G for ATP Hydrolysis MakesATP Useful to the CellThe ATP Synthase Is a Nanomachine that Produces ATP byRotary CatalysisProton-driven Turbines Are of Ancient OriginMitochondrial Cristae Help to Make ATP Synthesis EfficientSpecial Transport Proteins Exchange ATP and ADP Throughthe Inner MembraneChemiosmotic Mechanisms First Arose in BacteriaSummaryCHLOROPLASTS AND PHOTOSYNTHESISChloroplasts Resemble Mitochondria But Have a SeparateThylakoid CompartmentChloroplasts Capture Energy from Sunlight and Use It to FixCarbonCarbon Fixation Uses ATP and NADPH to Convert CO2 intoSugarsSugars Generated by Carbon Fixation Can Be Stored asStarch or Consumed to Produce ATPThe Thylakoid Membranes of Chloroplasts Contain the ProteinComplexes Required for Photosynthesis and ATP GenerationChlorophyll–Protein Complexes Can Transfer Either ExcitationEnergy or ElectronsA Photosystem Consists of an Antenna Complex and a ReactionCenterThe Thylakoid Membrane Contains Two Different PhotosystemsWorking in Series712712713714715716718719720721722722722723724725726727728729729730731731732734735735736737738740741741742743744744746746748748750750752753755757758758759761762763763763764764766768768770772773774774774776777778779780782782782783784785786787788789DETAILED CONTENTSPhotosystem II Uses a Manganese Cluster to WithdrawElectrons From WaterThe Cytochrome b6-f Complex Connects Photosystem II toPhotosystem IPhotosystem I Carries Out the Second Charge-SeparationStep in the Z SchemeThe Chloroplast ATP Synthase Uses the Proton GradientGenerated by the Photosynthetic Light Reactions toProduce ATPAll Photosynthetic Reaction Centers Have Evolved Froma Common AncestorThe Proton-Motive Force for ATP Production in Mitochondriaand Chloroplasts Is Essentially the SameChemiosmotic Mechanisms Evolved in StagesBy Providing an Inexhaustible Source of Reducing Power,Photosynthetic Bacteria Overcame a Major EvolutionaryObstacleThe Photosynthetic Electron-Transport Chains of CyanobacteriaProduced Atmospheric Oxygen and Permitted NewLife-FormsSummaryTHE GENETIC SYSTEMS OF MITOCHONDRIA ANDCHLOROPLASTSThe Genetic Systems of Mitochondria and Chloroplasts ResembleThose of ProkaryotesOver Time, Mitochondria and Chloroplasts Have Exported Mostof Their Genes to the Nucleus by Gene TransferThe Fission and Fusion of Mitochondria Are TopologicallyComplex ProcessesAnimal Mitochondria Contain the Simplest Genetic SystemsKnownMitochondria Have a Relaxed Codon Usage and Can Have aVariant Genetic CodeChloroplasts and Bacteria Share Many Striking SimilaritiesOrganelle Genes Are Maternally Inherited in Animals and PlantsMutations in Mitochondrial DNA Can Cause Severe InheritedDiseasesThe Accumulation of Mitochondrial DNA Mutations Is aContributor to AgingWhy Do Mitochondria and Chloroplasts Maintain a CostlySeparate System for DNA Transcription and Translation?SummaryProblemsReferencesChapter 15 Cell SignalingPRINCIPLES OF CELL SIGNALINGExtracellular Signals Can Act Over Short or Long DistancesExtracellular Signal Molecules Bind to Specific ReceptorsEach Cell Is Programmed to Respond to Specific Combinationsof Extracellular SignalsThere Are Three Major Classes of Cell-Surface Receptor ProteinsCell-Surface Receptors Relay Signals Via Intracellular SignalingMoleculesIntracellular Signals Must Be Specific and Precise in a NoisyCytoplasmIntracellular Signaling Complexes Form at Activated ReceptorsModular Interaction Domains Mediate Interactions BetweenIntracellular Signaling ProteinsThe Relationship Between Signal and Response Varies in DifferentSignaling PathwaysThe Speed of a Response Depends on the Turnover of SignalingMoleculesCells Can Respond Abruptly to a Gradually Increasing SignalPositive Feedback Can Generate an All-or-None ResponseNegative Feedback is a Common Motif in Signaling SystemsCells Can Adjust Their Sensitivity to a SignalSummarySIGNALING THROUGH G-PROTEIN-COUPLED RECEPTORSTrimeric G Proteins Relay Signals From GPCRsSome G Proteins Regulate the Production of Cyclic AMPCyclic-AMP-Dependent Protein Kinase (PKA) Mediates Mostof the Effects of Cyclic AMPxxix790791792793793794794796796798800800801802803804806807807808808809809811813813814815816818819820822822824825827828829830831832832833834Some G Proteins Signal Via PhospholipidsCa2+ Functions as a Ubiquitous Intracellular MediatorFeedback Generates Ca2+ Waves and OscillationsCa2+/Calmodulin-Dependent Protein Kinases MediateMany Responses to Ca2+ SignalsSome G Proteins Directly Regulate Ion ChannelsSmell and Vision Depend on GPCRs That Regulate Ion ChannelsNitric Oxide Is a Gaseous Signaling Mediator That PassesBetween CellsSecond Messengers and Enzymatic Cascades Amplify SignalsGPCR Desensitization Depends on Receptor PhosphorylationSummarySIGNALING THROUGH ENZYME-COUPLED RECEPTORSActivated Receptor Tyrosine Kinases (RTKs) PhosphorylateThemselvesPhosphorylated Tyrosines on RTKs Serve as Docking Sites forIntracellular Signaling ProteinsProteins with SH2 Domains Bind to Phosphorylated TyrosinesThe GTPase Ras Mediates Signaling by Most RTKsRas Activates a MAP Kinase Signaling ModuleScaffold Proteins Help Prevent Cross-talk Between ParallelMAP Kinase ModulesRho Family GTPases Functionally Couple Cell-Surface Receptorsto the CytoskeletonPI 3-Kinase Produces Lipid Docking Sites in the PlasmaMembraneThe PI-3-Kinase–Akt Signaling Pathway Stimulates AnimalCells to Survive and GrowRTKs and GPCRs Activate Overlapping Signaling PathwaysSome Enzyme-Coupled Receptors Associate with CytoplasmicTyrosine KinasesCytokine Receptors Activate the JAK–STAT Signaling PathwayProtein Tyrosine Phosphatases Reverse Tyrosine PhosphorylationsSignal Proteins of the TGFβ Superfamily Act Through ReceptorSerine/Threonine Kinases and SmadsSummaryALTERNATIVE SIGNALING ROUTES IN GENE REGULATIONThe Receptor Notch Is a Latent Transcription Regulatory ProteinWnt Proteins Bind to Frizzled Receptors and Inhibit theDegradation of β-CateninHedgehog Proteins Bind to Patched, Relieving Its Inhibition ofSmoothenedMany Stressful and Inflammatory Stimuli Act Through anNFκB-Dependent Signaling PathwayNuclear Receptors Are Ligand-Modulated TranscriptionRegulatorsCircadian Clocks Contain Negative Feedback Loops ThatControl Gene ExpressionThree Proteins in a Test Tube Can Reconstitute a CyanobacterialCircadian ClockSummarySIGNALING IN PLANTSMulticellularity and Cell Communication Evolved Independentlyin Plants and AnimalsReceptor Serine/Threonine Kinases Are the Largest Class ofCell-Surface Receptors in PlantsEthylene Blocks the Degradation of Specific TranscriptionRegulatory Proteins in the NucleusRegulated Positioning of Auxin Transporters Patterns PlantGrowthPhytochromes Detect Red Light, and Cryptochromes DetectBlue LightSummaryProblemsReferencesChapter 16 The CytoskeletonFUNCTION AND ORIGIN OF THE CYTOSKELETONCytoskeletal Filaments Adapt to Form Dynamic or StableStructuresThe Cytoskeleton Determines Cellular Organization and PolarityFilaments Assemble from Protein Subunits That Impart SpecificPhysical and Dynamic Properties836838838840843843846848848849850850852852854855857858859860861862863864865866867867868871873874876878879880880881881882883885886887889889890892893xxxDETAILED CONTENTSAccessory Proteins and Motors Regulate Cytoskeletal FilamentsBacterial Cell Organization and Division Depend on Homologsof Eukaryotic Cytoskeletal ProteinsSummaryACTIN AND ACTIN-BINDING PROTEINSActin Subunits Assemble Head-to-Tail to Create Flexible, PolarFilamentsNucleation Is the Rate-Limiting Step in the Formation of ActinFilamentsActin Filaments Have Two Distinct Ends That Grow at DifferentRatesATP Hydrolysis Within Actin Filaments Leads to Treadmilling atSteady StateThe Functions of Actin Filaments Are Inhibited by Both Polymerstabilizing and Polymer-destabilizing ChemicalsActin-Binding Proteins Influence Filament Dynamics andOrganizationMonomer Availability Controls Actin Filament AssemblyActin-Nucleating Factors Accelerate Polymerization andGenerate Branched or Straight FilamentsActin-Filament-Binding Proteins Alter Filament DynamicsSevering Proteins Regulate Actin Filament DepolymerizationHigher-Order Actin Filament Arrays Influence CellularMechanical Properties and SignalingBacteria Can Hijack the Host Actin CytoskeletonSummaryMYOSIN AND ACTINActin-Based Motor Proteins Are Members of the MyosinSuperfamilyMyosin Generates Force by Coupling ATP Hydrolysis toConformational ChangesSliding of Myosin II Along Actin Filaments Causes Musclesto ContractA Sudden Rise in Cytosolic Ca2+ Concentration InitiatesMuscle ContractionHeart Muscle Is a Precisely Engineered MachineActin and Myosin Perform a Variety of Functions in Non-MuscleCellsSummaryMICROTUBULESMicrotubules Are Hollow Tubes Made of ProtofilamentsMicrotubules Undergo Dynamic InstabilityMicrotubule Functions Are Inhibited by Both Polymer-stabilizingand Polymer-destabilizing DrugsA Protein Complex Containing γ-Tubulin Nucleates MicrotubulesMicrotubules Emanate from the Centrosome in Animal CellsMicrotubule-Binding Proteins Modulate Filament Dynamicsand OrganizationMicrotubule Plus-End-Binding Proteins Modulate MicrotubuleDynamics and AttachmentsTubulin-Sequestering and Microtubule-Severing ProteinsDestabilize MicrotubulesTwo Types of Motor Proteins Move Along MicrotubulesMicrotubules and Motors Move Organelles and VesiclesConstruction of Complex Microtubule Assemblies RequiresMicrotubule Dynamics and Motor ProteinsMotile Cilia and Flagella Are Built from Microtubules and DyneinsPrimary Cilia Perform Important Signaling Functions inAnimal CellsSummaryINTERMEDIATE FILAMENTS AND SEPTINSIntermediate Filament Structure Depends on the Lateral Bundlingand Twisting of Coiled-CoilsIntermediate Filaments Impart Mechanical Stability to Animal CellsLinker Proteins Connect Cytoskeletal Filaments and Bridge theNuclear EnvelopeSeptins Form Filaments That Regulate Cell PolaritySummaryCELL POLARIZATION AND MIGRATIONMany Cells Can Crawl Across a Solid SubstratumActin Polymerization Drives Plasma Membrane ProtrusionLamellipodia Contain All of the Machinery Required for Cell MotilityMyosin Contraction and Cell Adhesion Allow Cells to PullThemselves Forward894896898898898899900901904904906906907909911913914915915916916920923923925925926927929929930932932935936938940941942943944945946948949950951951951953954Cell Polarization Is Controlled by Members of the Rho ProteinFamilyExtracellular Signals Can Activate the Three Rho Protein FamilyMembersExternal Signals Can Dictate the Direction of Cell MigrationCommunication Among Cytoskeletal Elements CoordinatesWhole-Cell Polarization and LocomotionSummaryProblemsReferencesChapter 17 The Cell CycleOVERVIEW OF THE CELL CYCLEThe Eukaryotic Cell Cycle Usually Consists of Four PhasesCell-Cycle Control Is Similar in All EukaryotesCell-Cycle Progression Can Be Studied in Various WaysSummaryTHE CELL-CYCLE CONTROL SYSTEMThe Cell-Cycle Control System Triggers the Major Events ofthe Cell CycleThe Cell-Cycle Control System Depends on Cyclically ActivatedCyclin-Dependent Protein Kinases (Cdks)Cdk Activity Can Be Suppressed By Inhibitory Phosphorylationand Cdk Inhibitor Proteins (CKIs)Regulated Proteolysis Triggers the Metaphase-to-AnaphaseTransitionCell-Cycle Control Also Depends on Transcriptional RegulationThe Cell-Cycle Control System Functions as a Network ofBiochemical SwitchesSummaryS PHASES-Cdk Initiates DNA Replication Once Per CycleChromosome Duplication Requires Duplication of ChromatinStructureCohesins Hold Sister Chromatids TogetherSummaryMITOSISM-Cdk Drives Entry Into MitosisDephosphorylation Activates M-Cdk at the Onset of MitosisCondensin Helps Configure Duplicated Chromosomes forSeparationThe Mitotic Spindle Is a Microtubule-Based MachineMicrotubule-Dependent Motor Proteins Govern SpindleAssembly and FunctionMultiple Mechanisms Collaborate in the Assembly of a BipolarMitotic SpindleCentrosome Duplication Occurs Early in the Cell CycleM-Cdk Initiates Spindle Assembly in ProphaseThe Completion of Spindle Assembly in Animal Cells RequiresNuclear-Envelope BreakdownMicrotubule Instability Increases Greatly in MitosisMitotic Chromosomes Promote Bipolar Spindle AssemblyKinetochores Attach Sister Chromatids to the SpindleBi-orientation Is Achieved by Trial and ErrorMultiple Forces Act on Chromosomes in the SpindleThe APC/C Triggers Sister-Chromatid Separation and theCompletion of MitosisUnattached Chromosomes Block Sister-Chromatid Separation:The Spindle Assembly CheckpointChromosomes Segregate in Anaphase A and BSegregated Chromosomes Are Packaged in Daughter Nucleiat TelophaseSummaryCYTOKINESISActin and Myosin II in the Contractile Ring Generate the Forcefor CytokinesisLocal Activation of RhoA Triggers Assembly and Contractionof the Contractile RingThe Microtubules of the Mitotic Spindle Determine the Planeof Animal Cell DivisionThe Phragmoplast Guides Cytokinesis in Higher PlantsMembrane-Enclosed Organelles Must Be Distributed toDaughter Cells During Cytokinesis95595895895996096096296396396496596696796796796897097097197297497497497597797797897897897998298398498498598598698698798899099299399499599599699699799710001001DETAILED CONTENTSSome Cells Reposition Their Spindle to Divide AsymmetricallyMitosis Can Occur Without CytokinesisThe G1 Phase Is a Stable State of Cdk InactivitySummaryMEIOSISMeiosis Includes Two Rounds of Chromosome SegregationDuplicated Homologs Pair During Meiotic ProphaseHomolog Pairing Culminates in the Formation of a SynaptonemalComplexHomolog Segregation Depends on Several Unique Featuresof Meiosis ICrossing-Over Is Highly RegulatedMeiosis Frequently Goes WrongSummaryCONTROL OF CELL DIVISION AND CELL GROWTHMitogens Stimulate Cell DivisionCells Can Enter a Specialized Nondividing StateMitogens Stimulate G1-Cdk and G1/S-Cdk ActivitiesDNA Damage Blocks Cell Division: The DNA Damage ResponseMany Human Cells Have a Built-In Limitation on the Numberof Times They Can DivideAbnormal Proliferation Signals Cause Cell-Cycle Arrest orApoptosis, Except in Cancer CellsCell Proliferation is Accompanied by Cell GrowthProliferating Cells Usually Coordinate Their Growth and DivisionSummaryProblemsReferencesChapter 18 Cell DeathApoptosis Eliminates Unwanted CellsApoptosis Depends on an Intracellular Proteolytic CascadeThat Is Mediated by CaspasesCell-Surface Death Receptors Activate the Extrinsic Pathwayof ApoptosisThe Intrinsic Pathway of Apoptosis Depends on MitochondriaBcl2 Proteins Regulate the Intrinsic Pathway of ApoptosisIAPs Help Control CaspasesExtracellular Survival Factors Inhibit Apoptosis in Various WaysPhagocytes Remove the Apoptotic CellEither Excessive or Insufficient Apoptosis Can Contribute toDiseaseSummaryProblemsReferencesChapter 19 Cell Junctions and the ExtracellularMatrixCELL–CELL JUNCTIONSCadherins Form a Diverse Family of Adhesion MoleculesCadherins Mediate Homophilic AdhesionCadherin-Dependent Cell–Cell Adhesion Guides theOrganization of Developing TissuesEpithelial–Mesenchymal Transitions Depend on Control ofCadherinsCatenins Link Classical Cadherins to the Actin CytoskeletonAdherens Junctions Respond to Forces Generated by the ActinCytoskeletonTissue Remodeling Depends on the Coordination of ActinMediated Contraction With Cell–Cell AdhesionDesmosomes Give Epithelia Mechanical StrengthTight Junctions Form a Seal Between Cells and a FenceBetween Plasma Membrane DomainsTight Junctions Contain Strands of Transmembrane AdhesionProteinsScaffold Proteins Organize Junctional Protein ComplexesGap Junctions Couple Cells Both Electrically and MetabolicallyA Gap-Junction Connexon Is Made of Six TransmembraneConnexin SubunitsIn Plants, Plasmodesmata Perform Many of the Same Functionsas Gap JunctionsSelectins Mediate Transient Cell–Cell Adhesions in theBloodstreamxxxi100110021002100410041004100610061008100910101010101010111012101210141016101610161018101810191020102110211022102410251025102910291030103110321033103410351038103810381040104210421042104310451047104710491050105110531054Members of the Immunoglobulin Superfamily MediateCa2+-Independent Cell–Cell AdhesionSummaryTHE EXTRACELLULAR MATRIX OF ANIMALSThe Extracellular Matrix Is Made and Oriented by the CellsWithin ItGlycosaminoglycan (GAG) Chains Occupy Large Amounts ofSpace and Form Hydrated GelsHyaluronan Acts as a Space Filler During Tissue Morphogenesisand RepairProteoglycans Are Composed of GAG Chains CovalentlyLinked to a Core ProteinCollagens Are the Major Proteins of the Extracellular MatrixSecreted Fibril-Associated Collagens Help Organize the FibrilsCells Help Organize the Collagen Fibrils They Secrete byExerting Tension on the MatrixElastin Gives Tissues Their ElasticityFibronectin and Other Multidomain Glycoproteins HelpOrganize the MatrixFibronectin Binds to IntegrinsTension Exerted by Cells Regulates the Assembly ofFibronectin FibrilsThe Basal Lamina Is a Specialized Form of Extracellular MatrixLaminin and Type IV Collagen Are Major Components of theBasal LaminaBasal Laminae Have Diverse FunctionsCells Have to Be Able to Degrade Matrix, as Well as Make ItMatrix Proteoglycans and Glycoproteins Regulate theActivities of Secreted ProteinsSummaryCELL–MATRIX JUNCTIONSIntegrins Are Transmembrane Heterodimers That Link theExtracellular Matrix to the CytoskeletonIntegrin Defects Are Responsible for Many Genetic DiseasesIntegrins Can Switch Between an Active and an InactiveConformationIntegrins Cluster to Form Strong AdhesionsExtracellular Matrix Attachments Act Through Integrins toControl Cell Proliferation and SurvivalIntegrins Recruit Intracellular Signaling Proteins at Sites ofCell–Matrix AdhesionCell–Matrix Adhesions Respond to Mechanical ForcesSummaryTHE PLANT CELL WALLThe Composition of the Cell Wall Depends on the Cell TypeThe Tensile Strength of the Cell Wall Allows Plant Cells toDevelop Turgor PressureThe Primary Cell Wall Is Built from Cellulose MicrofibrilsInterwoven with a Network of Pectic PolysaccharidesOriented Cell Wall Deposition Controls Plant Cell GrowthMicrotubules Orient Cell Wall DepositionSummaryProblemsReferencesChapter 20 CancerCANCER AS A MICROEVOLUTIONARY PROCESSCancer Cells Bypass Normal Proliferation Controls andColonize Other TissuesMost Cancers Derive from a Single Abnormal CellCancer Cells Contain Somatic MutationsA Single Mutation Is Not Enough to Change a Normal Cellinto a Cancer CellCancers Develop Gradually from Increasingly Aberrant CellsTumor Progression Involves Successive Rounds of RandomInherited Change Followed by Natural SelectionHuman Cancer Cells Are Genetically UnstableCancer Cells Display an Altered Control of GrowthCancer Cells Have an Altered Sugar MetabolismCancer Cells Have an Abnormal Ability to Survive Stress andDNA DamageHuman Cancer Cells Escape a Built-in Limit to Cell ProliferationThe Tumor Microenvironment Influences Cancer Development1055105610571057105810591059106110631064106510661067106810681069107010721073107410741075107610771079107910791080108110811082108310831085108610871087108910911091109210931094109410951096109710981098109910991100xxxiiDETAILED CONTENTSCancer Cells Must Survive and Proliferate in a ForeignEnvironmentMany Properties Typically Contribute to Cancerous GrowthSummaryCANCER-CRITICAL GENES: HOW THEY ARE FOUNDAND WHAT THEY DOThe Identification of Gain-of-Function and Loss-of-FunctionCancer Mutations Has Traditionally Required DifferentMethodsRetroviruses Can Act as Vectors for Oncogenes That Alter CellBehaviorDifferent Searches for Oncogenes Converged on the SameGene—RasGenes Mutated in Cancer Can Be Made Overactive in ManyWaysStudies of Rare Hereditary Cancer Syndromes First IdentifiedTumor Suppressor GenesBoth Genetic and Epigenetic Mechanisms Can InactivateTumor Suppressor GenesSystematic Sequencing of Cancer Cell Genomes HasTransformed Our Understanding of the DiseaseMany Cancers Have an Extraordinarily Disrupted GenomeMany Mutations in Tumor Cells are Merely PassengersAbout One Percent of the Genes in the Human Genome AreCancer-CriticalDisruptions in a Handful of Key Pathways Are Common toMany CancersMutations in the PI3K/Akt/mTOR Pathway Drive Cancer Cellsto GrowMutations in the p53 Pathway Enable Cancer Cells to Surviveand Proliferate Despite Stress and DNA DamageGenome Instability Takes Different Forms in Different CancersCancers of Specialized Tissues Use Many Different Routes toTarget the Common Core Pathways of CancerStudies Using Mice Help to Define the Functions of CancerCritical GenesCancers Become More and More Heterogeneous as TheyProgressThe Changes in Tumor Cells That Lead to Metastasis AreStill Largely a MysteryA Small Population of Cancer Stem Cells May Maintain ManyTumorsThe Cancer Stem-Cell Phenomenon Adds to the Difficultyof Curing CancerColorectal Cancers Evolve Slowly Via a Succession of VisibleChangesA Few Key Genetic Lesions Are Common to a Large Fractionof Colorectal CancersSome Colorectal Cancers Have Defects in DNA Mismatch RepairThe Steps of Tumor Progression Can Often Be Correlatedwith Specific MutationsSummaryCANCER PREVENTION AND TREATMENT: PRESENT ANDFUTUREEpidemiology Reveals That Many Cases of Cancer ArePreventableSensitive Assays Can Detect Those Cancer-Causing Agentsthat Damage DNAFifty Percent of Cancers Could Be Prevented by Changesin LifestyleViruses and Other Infections Contribute to a SignificantProportion of Human CancersCancers of the Uterine Cervix Can Be Prevented by VaccinationAgainst Human PapillomavirusInfectious Agents Can Cause Cancer in a Variety of WaysThe Search for Cancer Cures Is Difficult but Not HopelessTraditional Therapies Exploit the Genetic Instability and Lossof Cell-Cycle Checkpoint Responses in Cancer CellsNew Drugs Can Kill Cancer Cells Selectively by TargetingSpecific MutationsPARP Inhibitors Kill Cancer Cells That Have Defects in Brca1or Brca2 GenesSmall Molecules Can Be Designed to Inhibit SpecificOncogenic Proteins11011103110311041104110511061106110711081109111111111112111311141115111611171117111811191120112111221123112411251126112711271127112811291131113211321132113311331135Many Cancers May Be Treatable by Enhancing the ImmuneResponse Against the Specific TumorCancers Evolve Resistance to TherapiesCombination Therapies May Succeed Where Treatments withOne Drug at a Time FailWe Now Have the Tools to Devise Combination TherapiesTailored to the Individual PatientSummaryProblemsReferencesChapter 21 Development of MulticellularOrganismsOVERVIEW OF DEVELOPMENTConserved Mechanisms Establish the Basic Animal Body PlanThe Developmental Potential of Cells Becomes ProgressivelyRestrictedCell Memory Underlies Cell Decision-MakingSeveral Model Organisms Have Been Crucial for UnderstandingDevelopmentGenes Involved in Cell–Cell Communication and TranscriptionalControl Are Especially Important for Animal DevelopmentRegulatory DNA Seems Largely Responsible for the DifferencesBetween Animal SpeciesSmall Numbers of Conserved Cell–Cell Signaling PathwaysCoordinate Spatial PatterningThrough Combinatorial Control and Cell Memory, SimpleSignals Can Generate Complex PatternsMorphogens Are Long-Range Inductive Signals That ExertGraded EffectsLateral Inhibition Can Generate Patterns of Different Cell TypesShort-Range Activation and Long-Range Inhibition CanGenerate Complex Cellular PatternsAsymmetric Cell Division Can Also Generate DiversityInitial Patterns Are Established in Small Fields of Cells andRefined by Sequential Induction as the Embryo GrowsDevelopmental Biology Provides Insights into Disease andTissue MaintenanceSummaryMECHANISMS OF PATTERN FORMATIONDifferent Animals Use Different Mechanisms to Establish TheirPrimary Axes of PolarizationStudies in Drosophila Have Revealed the Genetic ControlMechanisms Underlying DevelopmentEgg-Polarity Genes Encode Macromolecules Deposited in theEgg to Organize the Axes of the Early Drosophila EmbryoThree Groups of Genes Control Drosophila Segmentation Alongthe A-P AxisA Hierarchy of Gene Regulatory Interactions Subdivides theDrosophila EmbryoEgg-Polarity, Gap, and Pair-Rule Genes Create a TransientPattern That Is Remembered by Segment-Polarity andHox GenesHox Genes Permanently Pattern the A-P AxisHox Proteins Give Each Segment Its IndividualityHox Genes Are Expressed According to Their Order in theHox ComplexTrithorax and Polycomb Group Proteins Enable the HoxComplexes to Maintain a Permanent Record of PositionalInformationThe D-V Signaling Genes Create a Gradient of the TranscriptionRegulator DorsalA Hierarchy of Inductive Interactions Subdivides the VertebrateEmbryoA Competition Between Secreted Signaling Proteins Patternsthe Vertebrate EmbryoThe Insect Dorsoventral Axis Corresponds to the VertebrateVentral-Dorsal AxisHox Genes Control the Vertebrate A-P AxisSome Transcription Regulators Can Activate a Program ThatDefines a Cell Type or Creates an Entire OrganNotch-Mediated Lateral Inhibition Refines Cellular SpacingPatterns113711391139114011411141114311451147114711481148114811491149115011501151115111521153115311541154115511551157115711591159116011621163116311641164116611681169116911701171DETAILED CONTENTSAsymmetric Cell Divisions Make Sister Cells DifferentDifferences in Regulatory DNA Explain Morphological DifferencesSummaryDEVELOPMENTAL TIMINGMolecular Lifetimes Play a Critical Part in Developmental TimingA Gene-Expression Oscillator Acts as a Clock to ControlVertebrate SegmentationIntracellular Developmental Programs Can Help Determinethe Time-Course of a Cell’s DevelopmentCells Rarely Count Cell Divisions to Time Their DevelopmentMicroRNAs Often Regulate Developmental TransitionsHormonal Signals Coordinate the Timing of DevelopmentalTransitionsEnvironmental Cues Determine the Time of FloweringSummaryMORPHOGENESISCell Migration Is Guided by Cues in the Cell’s EnvironmentThe Distribution of Migrant Cells Depends on Survival FactorsChanging Patterns of Cell Adhesion Molecules Force CellsInto New ArrangementsRepulsive Interactions Help Maintain Tissue BoundariesGroups of Similar Cells Can Perform Dramatic CollectiveRearrangementsPlanar Cell Polarity Helps Orient Cell Structure and Movement inDeveloping EpitheliaInteractions Between an Epithelium and Mesenchyme GenerateBranching Tubular StructuresAn Epithelium Can Bend During Development to Form a Tubeor VesicleSummaryGROWTHThe Proliferation, Death, and Size of Cells Determine OrganismSizeAnimals and Organs Can Assess and Regulate Total Cell MassExtracellular Signals Stimulate or Inhibit GrowthSummaryNEURAL DEVELOPMENTNeurons Are Assigned Different Characters According to theTime and Place of Their BirthThe Growth Cone Pilots Axons Along Specific Routes TowardTheir TargetsA Variety of Extracellular Cues Guide Axons to their TargetsThe Formation of Orderly Neural Maps Depends on NeuronalSpecificityBoth Dendrites and Axonal Branches From the Same NeuronAvoid One AnotherTarget Tissues Release Neurotrophic Factors That ControlNerve Cell Growth and SurvivalFormation of Synapses Depends on Two-Way CommunicationBetween Neurons and Their Target CellsSynaptic Pruning Depends on Electrical Activity and SynapticSignalingNeurons That Fire Together Wire TogetherSummaryProblemsReferencesChapter 22 Stem Cells and Tissue RenewalSTEM CELLS AND RENEWAL IN EPITHELIAL TISSUESThe Lining of the Small Intestine Is Continually RenewedThrough Cell Proliferation in the CryptsStem Cells of the Small Intestine Lie at or Near the Base ofEach CryptThe Two Daughters of a Stem Cell Face a ChoiceWnt Signaling Maintains the Gut Stem-Cell CompartmentStem Cells at the Crypt Base Are Multipotent, Giving Rise tothe Full Range of Differentiated Intestinal Cell TypesThe Two Daughters of a Stem Cell Do Not Always Have toBecome DifferentPaneth Cells Create the Stem-Cell NicheA Single Lgr5-expressing Cell in Culture Can Generate an EntireOrganized Crypt-Villus Systemxxxiii11731174117511761176117711791180118011821182118411841185118611871188118811891190119211931193119411941196119711981199120112021204120612081209121112111213121312151217121712181219121912201220122212221223Ephrin–Eph Signaling Drives Segregation of the Different GutCell TypesNotch Signaling Controls Gut Cell Diversification and HelpsMaintain the Stem-Cell StateThe Epidermal Stem-Cell System Maintains a Self-RenewingWaterproof BarrierTissue Renewal That Does Not Depend on Stem Cells: InsulinSecreting Cells in the Pancreas and Hepatocytes in the LiverSome Tissues Lack Stem Cells and Are Not RenewableSummaryFIBROBLASTS AND THEIR TRANSFORMATIONS:THE CONNECTIVE-TISSUE CELL FAMILYFibroblasts Change Their Character in Response to Chemicaland Physical SignalsOsteoblasts Make Bone MatrixBone Is Continually Remodeled by the Cells Within ItOsteoclasts Are Controlled by Signals From OsteoblastsSummaryGENESIS AND REGENERATION OF SKELETAL MUSCLEMyoblasts Fuse to Form New Skeletal Muscle FibersSome Myoblasts Persist as Quiescent Stem Cells in the AdultSummaryBLOOD VESSELS, LYMPHATICS, AND ENDOTHELIAL CELLSEndothelial Cells Line All Blood Vessels and LymphaticsEndothelial Tip Cells Pioneer AngiogenesisTissues Requiring a Blood Supply Release VEGFSignals from Endothelial Cells Control Recruitment of Pericytesand Smooth Muscle Cells to Form the Vessel WallSummaryA HIERARCHICAL STEM-CELL SYSTEM: BLOOD CELLFORMATIONRed Blood Cells Are All Alike; White Blood Cells Can BeGrouped in Three Main ClassesThe Production of Each Type of Blood Cell in the Bone MarrowIs Individually ControlledBone Marrow Contains Multipotent Hematopoietic Stem Cells,Able to Give Rise to All Classes of Blood CellsCommitment Is a Stepwise ProcessDivisions of Committed Progenitor Cells Amplify the Number ofSpecialized Blood CellsStem Cells Depend on Contact Signals From Stromal CellsFactors That Regulate Hematopoiesis Can Be Analyzed in CultureErythropoiesis Depends on the Hormone ErythropoietinMultiple CSFs Influence Neutrophil and Macrophage ProductionThe Behavior of a Hematopoietic Cell Depends Partly on ChanceRegulation of Cell Survival Is as Important as Regulation of CellProliferationSummaryREGENERATION AND REPAIRPlanarian Worms Contain Stem Cells That Can Regenerate aWhole New BodySome Vertebrates Can Regenerate Entire OrgansStem Cells Can Be Used Artificially to Replace Cells That AreDiseased or Lost: Therapy for Blood and EpidermisNeural Stem Cells Can Be Manipulated in Culture and Used toRepopulate the Central Nervous SystemSummaryCELL REPROGRAMMING AND PLURIPOTENT STEM CELLSNuclei Can Be Reprogrammed by Transplantation into ForeignCytoplasmReprogramming of a Transplanted Nucleus Involves DrasticEpigenetic ChangesEmbryonic Stem (ES) Cells Can Generate Any Part of the BodyA Core Set of Transcription Regulators Defines and Maintainsthe ES Cell StateFibroblasts Can Be Reprogrammed to Create InducedPluripotent Stem Cells (iPS Cells)Reprogramming Involves a Massive Upheaval of the GeneControl SystemAn Experimental Manipulation of Factors that Modify ChromatinCan Increase Reprogramming EfficienciesES and iPS Cells Can Be Guided to Generate Specific AdultCell Types and Even Whole Organs12241224122512261227122712281228122912301232123212321233123412351235123512361237123812381239123912401242124312431244124412441245124512461247124712471248124912501251125112521252125312541254125512561256xxxivDETAILED CONTENTSCells of One Specialized Type Can Be Forced toTransdifferentiate Directly Into AnotherES and iPS Cells Are Useful for Drug Discovery and Analysisof DiseaseSummaryProblemsReferencesChapter 23 Pathogens and Infection125812581260126012621263INTRODUCTION TO PATHOGENS AND THE HUMANMICROBIOTAThe Human Microbiota Is a Complex Ecological System That IsImportant for Our Development and HealthPathogens Interact with Their Hosts in Different WaysPathogens Can Contribute to Cancer, Cardiovascular Disease,and Other Chronic IllnessesPathogens Can Be Viruses, Bacteria, or EukaryotesBacteria Are Diverse and Occupy a Remarkable Variety ofEcological NichesBacterial Pathogens Carry Specialized Virulence GenesBacterial Virulence Genes Encode Effector Proteins and SecretionSystems to Deliver Effector Proteins to Host CellsFungal and Protozoan Parasites Have Complex Life CyclesInvolving Multiple FormsAll Aspects of Viral Propagation Depend on Host Cell MachinerySummaryCELL BIOLOGY OF INFECTIONPathogens Overcome Epithelial Barriers to Infect the HostPathogens That Colonize an Epithelium Must Overcome ItsProtective MechanismsExtracellular Pathogens Disturb Host Cells Without EnteringThemIntracellular Pathogens Have Mechanisms for Both Enteringand Leaving Host CellsViruses Bind to Virus Receptors at the Host Cell SurfaceViruses Enter Host Cells by Membrane Fusion, Pore Formation,or Membrane DisruptionBacteria Enter Host Cells by PhagocytosisIntracellular Eukaryotic Parasites Actively Invade Host CellsSome Intracellular Pathogens Escape from the Phagosomeinto the CytosolMany Pathogens Alter Membrane Traffic in the Host Cell toSurvive and ReplicateViruses and Bacteria Use the Host-Cell Cytoskeleton forIntracellular MovementViruses Can Take Over the Metabolism of the Host CellPathogens Can Evolve Rapidly by Antigenic VariationError-Prone Replication Dominates Viral EvolutionDrug-Resistant Pathogens Are a Growing ProblemSummaryProblemsReferencesChapter 24 The Innate and Adaptive ImmuneSystemsTHE INNATE IMMUNE SYSTEMEpithelial Surfaces Serve as Barriers to InfectionPattern Recognition Receptors (PRRs) Recognize ConservedFeatures of PathogensThere Are Multiple Classes of PRRsActivated PRRs Trigger an Inflammatory Response at Sites ofInfectionPhagocytic Cells Seek, Engulf, and Destroy PathogensComplement Activation Targets Pathogens for Phagocytosisor LysisVirus-Infected Cells Take Drastic Measures to Prevent ViralReplicationNatural Killer Cells Induce Virus-Infected Cells to Kill ThemselvesDendritic Cells Provide the Link Between the Innate andAdaptive Immune SystemsSummary126312641264126512661267126812691271127312751276127612761277127812791280128112821284128412861288128912911291129412941296129712981298129812991300130113021303130413051305OVERVIEW OF THE ADAPTIVE IMMUNE SYSTEMB Cells Develop in the Bone Marrow, T Cells in the ThymusImmunological Memory Depends On Both Clonal Expansionand Lymphocyte DifferentiationLymphocytes Continuously Recirculate Through PeripheralLymphoid OrgansImmunological Self-Tolerance Ensures That B and T CellsDo Not Attack Normal Host Cells and MoleculesSummaryB CELLS AND IMMUNOGLOBULINSB Cells Make Immunoglobulins (Igs) as Both Cell-SurfaceAntigen Receptors and Secreted AntibodiesMammals Make Five Classes of IgsIg Light and Heavy Chains Consist of Constant and VariableRegionsIg Genes Are Assembled From Separate Gene SegmentsDuring B Cell DevelopmentAntigen-Driven Somatic Hypermutation Fine-Tunes AntibodyResponsesB Cells Can Switch the Class of Ig They MakeSummaryT CELLS AND MHC PROTEINST Cell Receptors (TCRs) Are Ig-like HeterodimersActivated Dendritic Cells Activate Naïve T CellsT Cells Recognize Foreign Peptides Bound to MHC ProteinsMHC Proteins Are the Most Polymorphic Human ProteinsKnownCD4 and CD8 Co-receptors on T Cells Bind to Invariant Partsof MHC ProteinsDeveloping Thymocytes Undergo Negative and Positive SelectionCytotoxic T Cells Induce Infected Target Cells to Kill ThemselvesEffector Helper T Cells Help Activate Other Cells of the Innateand Adaptive Immune SystemsNaïve Helper T Cells Can Differentiate Into Different Types ofEffector T CellsBoth T and B Cells Require Multiple Extracellular Signals ForActivationMany Cell-Surface Proteins Belong to the Ig SuperfamilySummaryProblemsReferences13071308GlossaryG:1130913111313131513151315131613181319132113221323132413251326132613301331133213331335133513361338133913401342IndexI:1TablesT:11PARTIIIIIIIVVINTRODUCTION TO THE CELLCHAPTERCells and GenomesThe surface of our planet is populated by living things—curious, intricately organized chemical factories that take in matter from their surroundings and use theseraw materials to generate copies of themselves.