Часть 2 (1121000), страница 33
Текст из файла (страница 33)
r(v)66e pezrlrpaltcsNotstnuvt'tfnNcll_l'ldtAo)NOtIVZrUV'tn't'll)el)^) lle) eql :/ [ ra]deqf00t tOF CELLDIVISIONAND CELLGROWTHCONTROLRapid cyclin accumulation immediately after mitosis is not useful, however,for cells with cell cyclescontaining a G1phase.These cells employ severalmechanisms to prevent Cdk reactivation after mitosis. One mechanism uses anotherAPC/C-activating protein called Cdhl, a close relative of Cdc20.
Although bothCdhl and Cdc20 bind to and activate the APC/C, they differ in one importantrespect. \ArhereasM-Cdk activates the Cdc20-APC/C complex, it inhibits theCdhl-APC/C complex by directly phosphorylating Cdhl. As a result of this relationship, Cdhl-APC/C activity increasesin late mitosis after the Cdc20-APC/Ccomplex has initiated the destruction of M-cyclin. M-cyclin destruction therefore continues after mitosis: although Cdc20-APC/C activity has declined,Cdhl-APC/C activity is high (Figure l7-608)A second mechanism that suppresses Cdk activity in G1 depends on theincreased production of CKIs, the Cdk inhibitory proteins discussed earlier.Budding yeast cells, in which this mechanism is best understood, contain a CKIprotein called Sicl, which binds to and inactivates M-Cdk in late mitosis and G1.Like Cdhl, Sicl is inhibited by M-Cdk, which phosphorylates Sicl during mitosis and thereby promotes its ubiquitylation by SCF.Thus, Sicl and M-Cdk, likeCdhl and M-Cdk, inhibit each other.
As a result, the decline in M-Cdk activitythat occurs in late mitosis causesthe Sicl protein to accumulate, and this CKIhelps keep M-Cdk activity low after mitosis. A CKI protein called p27 (seeFigurel7-I9l17-19) may serve similar functions in animal cells.In most cells, decreasedtranscription of M-cyclin genes also inactivates MCdks in late mitosis. In budding yeast,for example, M-Cdk promotes the expression of these genes,resulting in a positive feedback loop.
This loop is turned offas cells exit from mitosis: the inactivation of M-Cdk by Cdhl and Sicl leads todecreasedM-cyclin gene transcription and thus decreasedM-cyclin synthesis.Gene regulatoryproteins that promote the expressionof G1/S- and S-cyclins arealso inhibited during G1.Thus, Cdhl-APC/C activation, CKI accumulation, and decreasedcyclin geneexpression act together to ensure that the early G1phase is a time when essentiallyall Cdk activity is suppressed. As in many other aspects of cell-cycle control, theuse of multiple regulatory mechanisms makes the suppression system robust, sothat it still operates with reasonable efficiency even if one mechanism fails.
So howdoes the cell escape from this stable Gr state to initiate a new cell cycle? Theanswer is that Gl/S-Cdk actMty, which rises in late Gr, releasesall the brakingmechanisms that suppress Cdk activity, as we describe in the next section'SummaryAfter mitosiscompletestheformation of a pair of daughter nuclei, cytokinesisfinishesthe cell cycle by diuiding the cell itself.
Cytokinesisdepends on a ring of actin andmyosin that contractsin late mitosis at a site midway betweenthe segregatedchromosomes.In animal cells,the positioning of the contractile ring is determined by signalsemanatingfrom the microtubules of the anaphasespindle.
Dephosphorylation of Cdktargets,which resultsfrom Cdk inactiuation in anaphase, triggerscytokinesisat thecorrecttime after anaphase.After cytokinesis,the cell entersa stableGt stateof low Cdkactiuity, where it awaits signals to enter a new cell cycle.ANDCELLGRO THOFCELLDIVISIONCONTROLA fertilized mouse egg and a fertilized human egg are similar in size, yet theyproduce animals of very different sizes.\Alhatfactors in the control of cell behavior in humans and mice are responsible for these size differences?The same fundamental question can be asked for each organ and tissue in an animal's body.\Alhat factors in the control of cell behavior explain the length of an elephant'strunk or the size of its brain or its liver? These questions are largely unanswered,at least in part because they have received relatively little attention comparedwith other questions in cell and developmental biology.
It is neverthelesspossible to say what the ingredients of an answer must be.11011102Chapter17:TheCell CycleThe size of an organ or organism depends mainly on its total cell mass,which depends on both the total number of cells and the size of the cells. Cellnumber, in turn, depends on the amounts of cell division and cell death. organand body size are therefore determined by three fundamental processes:cellgrowth, cell division, and cell death. Each is tightly regulated-both by intracellular programs and by extracellular signal molecules that control these programs.The extracellular signal molecules that regulate cell size and cell number aregenerally soluble secreted proteins, proteins bound to the surface of cells, orcomponents of the extracellular matrix.
They can be divided operationally intothree major classes:1. Mitogens, which stimulate cell division, primarily by triggering a wave ofGr/S-Cdk activity that relieves intracellular negative controls that otherwise block progress through the cell cycle.2. Growth factors, which stimulate cell growth (an increase in cell mass) bypromoting the synthesis of proteins and other macromolecules and byinhibiting their degradation.3.
suruiual facfors, which promote cell survival by suppressing the form ofprogrammed cell death known as apoptosis.Many extracellular signal molecules promote all of these processes,whileothers promote one or two of them. Indeed, the term growthfaAoris often usedinappropriately to describe a factor that has any of these activities. Even worse,the term cell growthis often used to mean an increasein cell numb er,or cell nroliferation.In addition to these three classesof stimulating signals,there are extracellular signal molecules that suppresscell proliferation, cell growth, or both; in general, Iessis known about them. There are also extracellular signal molecules thatactivate apoptosis.In this section, we focus primarily on how mitogens and other factors, suchas DNA damage, control the rate of cell division.
we then turn to the importantbut poorly understood problem of how a proliferating cell coordinates its growthwith cell division so as to maintain its appropriate size.We discussthe control ofcell survival and cell death by apoptosis in Chapter lg.microtubuleMitogensStimulateCellDivisionu-nicellularorganismstend to growand divideasfastasthey can,and their rateof proliferationdependslargelyon the availabilityof nutrientsin the environ-1[mPDGFis only one of over50proteinsthat areknornmto act asmitogens.Mostof theseproteins have a broad specificity.pDGII for example,can stimulatemany types of cells to divide, including fibroblasts,smooth musclecells,andFigure17-61A platelet.Plateletsareminiaturecellswithouta nucleus.Theycirculatein the bloodand helpstimulatebloodclottingat sitesof tissuedamage,therebypreventingexcessivebleeding.Theyalsoreleasevariousfactorsthatstimulatehealing.The plateletshownherehasbeencut in halfto show itssecretoryvesicles,someof whichcontainplatelet-derivedqrowth factor (PDGF).OF CELLDIVISIONAND CELLGROWTHCONTROLneuroglial cells.
Similarly, epidermal growth factor (EGD acts not only on epidermal cells but also on many other cell types, including both epithelial andnonepithelial cells. Some mitogens, however, have a narrow specificity; erythro'poietin, for example, only induces the proliferation of red blood cell precursors.Many mitogens, including PDGE also have other actions beside the stimulationof cell division: they can stimulate cell growth, survival, differentiation, ormigration, depending on the circumstances and the cell type.In some tissues,inhibitory extracellular signal proteins oppose the positiveregulators and thereby inhibit organ growth.
The best-understood inhibitorysignal proteins are TGFp and its relatives.TGFBinhibits the proliferation of several cell t1pes, either by blocking cell-cycle progression in G1 or by stimulatingapoptosis.NondividingCellsCanDelayDivisionby Enteringa SpecializedStateIn the absence of a mitogenic signal to proliferate, Cdk inhibition in Gt is maintained by the multiple mechanisms discussedearlier,and progressioninto a newcell cycle is blocked.
In some cases,cells partly disassembletheir cell-cycle control system and exit from the cycle to a specialized, nondividing state called G6.Most cells in our body are in Gs, but the molecular basis and reversibility ofthis state vary in different cell types.
Most of our neurons and skeletal muscle cells,for example, are in a terminally dffirentinted Ge state, inwhich their cell-cyclecontrol system is completely dismantled: the expression of the genes encodingvarious Cdks and cyclins are permanently turned off, and cell dMsion rarelyoccurs. Other cell types withdraw from the cell cycle only transiently and retainthe ability to reassemble the cell-cycle control system quickly and reenter thecycle. Most liver cells, for example, are in Gs, but they can be stimulated to dMdeif the liver is damaged. Still other t!?es of cells, including fibroblasts and someIymphocytes, withdraw from and re-enter the cell cycle repeatedly throughouttheir lifetime.Almost all the variation in cell-cycle length in the adult body occurs duringthe time the cell spends in G1or Go.By contrast, the time a cell takes to progressfrom the beginning of S phase through mitosis is usually brief (typically 12-24hours in mammals) and relatively constant, regardlessof the interval from onedivision to the next.ActivitiesMitogensStimulateGr-Cdkand GrlS-CdkFor the vast majority of animal cells, mitogens control the rate of cell division byacting in the Gr phase of the cell cycle.As discussedearlier,multiple mechanismsact during G1to suppressCdk activity and therebyblock entry into S phase.Mitogens release these brakes on Cdk activity, thereby allowing S phase to begin.As we discussin Chapter 15, mitogens interact with cell-surfacereceptors totrigger multiple intracellular signaling pathways.
One major pathway actsthrough the small GTPaseRas,which leads to the activation of a MAP kinase cascade.This leads to an increase in the production of gene regulatory proteins,including Myc. Myc is thought to promote cell-cycle entry by several mechanisms, one of which is to increase the expression of genes encoding G1 cyclins(D cyclins), thereby increasing Gr-Cdk (cyclin D-Cdk4) activity. As we discusslater, Myc also has a major role in stimulating the transcription of genes thatincrease cell growth.The key function of Gr-Cdk complexes in animal cells is to activate a groupof gene regulatory factors called the E2F proteins, which bind to specific DNAsequences in the promoters of a wide variety of genes that encode proteinsrequired for S-phase entry, including G1/S-cyclins, S-cyclins, and proteinsinvolved in DNA synthesis and chromosome duplication. In the absence ofmitogenic stimulation, E2F-dependent Seneexpressionis inhibited by an interaction between E2F and members of the retinoblastoma protein (Rb) family.11031104Chapter17:TheCellCyclemrtogenFigure 17 -62 Mechanismscontrollingcell-cycleentry and S-phaseinitiationinanimalcells.As discussedin Chapter15,mitogensbind to cell-surfacereceptorsto initiateintracellularsignalingpathways.One of the major pathwaysinvolvesactivationof the smallGTPaseRas,whichactivatesa MAPkinasecascade,leadingto increasedexpressionof numerousimmediateearly genes,includingthe geneencodingthe generegulatoryproteinMyc.Myc increasestheexpressionof many delayed-responsegenes,includingsomethat leadtoincreasedG1-Cdkactivity(cyclinD-Cdk4),whichtriggersthe phosphorylationofmembersof the Rbfamilyof proteins.Thisinactivatesthe Rb proteins,freeingthe generegulatoryproteinE2Ftoactivatethe transcriptionof G115genes,includingthe genesfor a G1lS-cyclin(cyclinE)and S-cyclin(cyclinA).TheresultingGrlS-Cdkand S-CdkactivitiesfurtherenhanceRb proteinphosphorylation,forminga positivefeedbackloop.E2Fproteinsalsostimulatethe transcriptionof theirowngenes,forminganotherpositivefeedbacklooo.I nasI+Ia c t i v a t i o no f g e n e r e g u l a t o r yp r o t e i ncYrosolIrflNUCLEUSIxn"*11,"*onI'generegulatorygluyc.*fproteinIdelayed-responsegene expresston)positivefeedbackG 1/S-cyclin(cyciln rlS-cyclin( c y c l i nA )active+S.CdKDNASYNTHESISi nactivatedE 2 Fp r o t e i ninactivated RbproteinF.?ffi"\A/hencells are stimulated to divide by mitogens, active Gr-cdk accumulates andin turn increase Rb protein phosphorylation and promote further E2F release(seeFigure 17-62).The central member of the Rb family, the Rb protein itself, was identifiedoriginally through studies of an inherited form of eye cancer in children, knonmas retinoblastoma (discussedin chapter 20).
![](https://s.studizba.com/z.php?f=/templates/si/i/noavatar.png&w=100&h=100&t=1"){kind=avatar}
