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Similarly, mutations that cause an overexpression of Myc stimulate excessive cellgrowth and proliferation and thereby promote the development of cancer.Surprisingly, however, when a hyperactivated form of Ras or Myc is experimentally overproduced in most normal cells, the result is not excessiveproliferation but the opposite: the cells undergo either cell-cycle arrest or apoptosis.The normal cell seems able to detect abnormal mitogenic stimulation, and itresponds by preventing further division. Such responseshelp prevent the survival and proliferation of cells with various cancer-promoting mutations.Although it is not knolrm how a cell detects excessivemitogenic stimulation,such stimulation often leads to the production of a cell-cycle inhibitor proteincalledArf which binds and inhibits Mdm2.
As discussedearlier, Mdm2 normally1"t071108Chapter17:TheCellCycleFigure 17-64 Cell-cyclearrestorapoptosisinduced by excessivestimulationof mitogenicpathways.Abnormallyhigh levelsof Myccausetheactivationof Arf,whichbindsand inhibitsp53 levelsMdm2 and therebyincreases(seeFigure17-60).Dependingon the cellp53type and extracellularconditions,then causeseithercell-cyclearrestorapoptosis.excessiveMyc productiona c t i v eM d m 2stable,active p53promotes p53 degradation. Activation of Arf therefore causes p53 levels toincrease,inducing either cell-cycle arrest or apoptosis (Figure lZ-64).How do cancer cells ever arise if these mechanisms block the division orsurvival of mutant cells with overactive proliferation signals?The answer is thatthe protective system is often inactivated in cancer cells by mutations in thegenes that encode essential components of the checkpoint responses,such asArf or p53 or the proteins that help activate them.Organismand OrganGrowthDependon CellGrowthFor an organism or organ to grow cell division is not enough.
If cells proliferatedwithout growing, theywould get progressivelysmaller and there would be no netincrease in total cell mass. In most proliferating cell populations, therefore, cellgrowth accompaniescell division. In single-celledorganisms such as yeasts,bothcell growth and cell division require only nutrients. In animals, by contrast, bothcell growth and cell proliferation depend on extracellular signal molecules, produced by other cells, which we call growth factors and mitogens, respectively.Like mitogens, the extracellular growth factors that stimulate animal cellgrowth bind to receptors on the cell surface and activate intracellular signalingpathways. These pathways stimulate the accumulation of proteins and othermacromolecules, and they do so by both increasing their rate of synthesis anddecreasing their rate of degradation.
They also trigger increased uptake of nutrients and production of the ArP required to fuel increased protein slmthesis. oneof the most important intracellular signaling pathways activated by growth factorreceptors involves the en4rme PI 3-kinase, which adds a phosphate from AIp tothe 3 position of inositol phospholipids in the plasma membrane.
As discussedinChapter 15, the activation of PI 3-kinase leads to the activation of a kinase calledToR, which lies at the heart of groMh regulatory pathways in all eucaryotes. ToRactivates many targets in the cell that stimulate metabolic processesand increaseprotein slmthesis. one target is a protein kinase called s6 kinase (s6&, whichphosphorylatesribosomal protein 56, increasingthe ability of ribosomes to translate a subset of mRNAs that mostly encode ribosomal components. ToR also indirectly activates a translation initiation factor called eIF4E and directly activatesgene regulatory proteins that promote the increased expression of genes encodingribosomal subunits (Figure f7-6S).ProliferatingcellsUsuallycoordinateTheirGrowthand DivisionFor proliferating cells to maintain a constant size, they must coordinate theirgrowth with cell division to ensure that cell size doubles with each division: ifcells grow too slowly, they will get smaller with each division, and if they grow1109CONTROLOFCELLDIVISIONAND CELLGROWTHgrowth factoraminoacids{Figure 17-65 Stimulationof cell growthby extracellulargrowth factors andin Chapter15, thenutrients.As discussedoccupationof cell-surfacereceptorsbygrowth factorsleadsto the activationofwhichpromotesproteinPl 3-kinase,througha complexsignalingsynthesispathwaythat leadsto the activationofthe proteinkinaseTOR;extracellularnutrientssuchasaminoacidsalsohelpactivateTORby an unknown pathway.toTORemploysmultiplemechanismsas shown;itstimulateproteinsynthesis,alsoinhibitsproteindegradation(notshown).Growthfactorsalsostimulateproductionof the geneincreasedregulatoryprotein Myc (not shown),ofthe transcriptionwhichactivatesvariousgenesthat promotecellis anmetabolismand growth.4E-BPinitiationinhibitorof the translationfactor elF4E."i,I,/activatedgrowthfactor receptorgeneregulatoryfactorsIVribosomesynthesisII55+lItoo fast, they will get larger with each division.
It is not clear how cells achievethis coordination, but it is likely to involve multiple mechanisms that vary in different organisms and even in different cell types of the same organism (Figurer7-66).Animal cell groMh and division are not always coordinated, however. Inmany cases,they are completely uncoupled to allow growth without division ordivision without growth.
Muscle cells and nerve cells, for example, can grow dramatically after they have permanently withdrawrl from the cell cycle. Similarly,the eggs of many animals grow to an extremely large size without dividing; afterfertilization, however, this relationship is reversed,and many rounds of divisionoccur without growth (seeFigure 17-9).Compared to cell division, there has been surprisingly little study of how cellsize is controlled in animals. As a result, it remains a mystery how cell size isdetermined and why different cell qpes in the same animal grow to be so different in size (Figure 17-67).
One of the best-understood casesin mammals is theadult sympathetic neuron, which has permanently withdrarnrn from the cellcycle. Its size depends on the amount of neruegrowth factor (NGF) secretedbythe target cells it innervates; the greater the amount of NGF the neuron hasaccessto, the larger it becomes.
It seemslikely that the genesa cell expressessetlimits on the size it can be, while extracellular signal molecules and nutrientsGROWTHFACTORMITOGENC E L LG R O W T HC E L LD I V I S I O NCELLGROWTHIItCELLDIVISION(A)(B)(c)cells,cellsizeisfor coordinatingcellgrowth and division.ln proliferatingFigure| 7-66 Potentialmechanismscouplingmaintainedby mechanismsthat coordinateratesof celldivisionand cellgrowth.Numerousalternativeof thesemechanismsarethoughtto exist,and differentcelltypesappearto employdifferentcombinations(A)In manycelltypes-particularlyyeast-the rateof celldivisionis governedby the rateof cellmechanisms.someminimalthreshold;in yeasts,it is mainlythegrowth,so that divisionoccursonlywhen growthrateachievesnutrientsthat regulatethe rateof cellgrowthand therebythe rateof celldivision'(B)Inlevelsof extracellularfactors(growthextracellularsomeanimalcelltypes,growthand divisioncaneachbe controlledby separateand cell sizedependson the relativelevelsof the two types of factors.factorsand mitogens,respectively),activating(C)Someextracellularfactorscan stimulateboth cellgrowthand celldivisionby simultaneouslyprogression.signalingpathwaysthat promotegrowthand other pathwaysthat promotecell-cycle1110Chapter17:TheCellCycleFigure 17-67 The sizedifferencebetween a neuron (from the retina)anda lymphocytein a mammal.Bothcellscontainthe sameamountof DNA.A neurongrowsprogressivelylargerafterit haspermanentlywithdrawnfrom the cellcycle.Duringthis time,the ratioof cytoplasmto DNAincreasesenormously(by a factorof morethan 10sfor someneurons).(Neuronfrom B.B.Boycott,in Essayson the NervousSystem[R.BellairsandE.G.Gray,edsl.Oxford,UK:ClarendonPress,1974.)regulate the size within these limits.
The challenge is to identify the relevantgenes and signal molecules for each cell type.NeighboringCellsCompetefor ExtracellularSignalProteins\Arhenmost types of mammalian cells are cultured in a dish in the presence ofserum, they adhere to the bottom of the dish, spread out, and divide until theyform a confluent monolayer. Each cell is attached to the dish and contacts itsneighbors on all sides.At this point, normal cells,unlike cancer cells, stop proliferating-a phenomenon known as density-dependentinhibition of cell diuision.This phenomenon was originally described in terms of "contact inhibition" of celldivision, but it is unlikely that cell-cell contact interactions are solely responsible.The cell population density at which cell proliferation ceasesin the confluentmonolayer increases as the concentration of serum in the medium increases.Moreover, if a stream of fresh culture medium is passedover a confluent layer offibroblasts to increase the supply of mitogens, the cells under the stream areinduced to divide (Figure r 7-68).
Thus, density-dependent inhibition of cell proliferation seems to reflect, in part at least, the ability of a cell to deplete themedium around itself of extracellular mitogens, thereby depriving its neighbors.This type of competition could be important for cells in tissues as well as inculture, becauseit prevents them from proliferating beyond a certain populationdensity, determined by the available amounts of mitogens, growth factors, andsurvival factors.
The amounts of these factors in tissues are usually limiting, inthat increasing their amounts results in an increase in cell number, cell size, orboth. Thus, the amounts of these factors in tissueshave important roles in determining cell size and number, and possibly the final size of the organ or tissue.The overall size of a tissue may also be governed in some casesby extracellular inhibitory factors.
Myostatin, for example, is a TGFB family member thatnormally inhibits the proliferation of myoblasts that fuse to form skeletal muscle cells.\A/henthe gene that encodes myostatin is deleted in mice, muscles growto be several times larger than normal. Remarkably, two breeds of cattle thatwere bred for large muscles have both turned out to have mutations in the geneencoding myostatin (Figure f 7-69).cells proliferateconfluent monolayer: cellsno longer proliferates t r e a mo f f r e s hm e d i u mp u m p e da c r o s sc e l l sneuronalymphocytef l o w o f m e d i u ms t i m u l a t e sc e l l p r o l i f e r a t i o nu n d e rt h e s t r e a mFigure17-68The effectof freshmediumon a confluentcell monolayer.Cellsin a confluentmonolayerdo not divide(grafl.fhecellsresumedividing(green)whenexposeddirectlyto freshculturemedium.Apparently,in the undisturbedconfluentmonolayer,proliferationhashaltedbecausethe mediumclosetothe cellsis depletedof mitogens,for whichthe cellscompete.1111CONTROLOFCELLDIVISIONANDCELLGROWTHFigure17-69 The effectsof a myostatinmutationon musclesize,The mutationin the massofleadsto a greatincreasein this Belgianmuscletissue,as illustratedBluebull.The BelgianBluewas producedby cattlebreedersand wasonly recentlyfoundto havea mutationin theMyostatingene.(FromH.L.Sweeney,Sci.Am.
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