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Mice in which both copies of thegene have been deleted or inactivated typically appear normal in all respectsexcept one-they universally develop cancer before l0 months of age. Theseobservations suggestthat p53 may have a function that is required only in special circumstances. Indeed, when normal cells are deprived of oxygen orexposed to treatments that damage DNA, such as ultraviolet light or gammarays, they raise their concentration of p53 protein by blocking the degradation ofthe molecule. The accumulation of p53 protein is seen also in cells where oncogenes such as Ras and Myc are unusually active, generating an abnormal stimuIus for cell division.In all these cases,the high level of p53 protein acts to limit the harm done.ther cell division, producing the phenomenon of replicative cell senescence(Figure 2o-40).
The protection that p53 provides is part of the reason why mutationsthat activate oncogenes such as Ras and Myc are not sufficient to create a tumor.protein performs its job mainly by acting as a gene regulatory protein> Indeed, the most common mutations observed in p53 in humantumors are in its DNA-binding domain, where they cripple the ability of p53 tobind to its DNA target sequences.As discussed in chapter 17, the p53 pioteinH Y P E R P R O L I F E R A T I VDEN AsrGNALsLltlTELOMEREDAMAGEss-onrirrrir,rtHYPoxlAtd:lllrs t a b l e ,a c t i v ep 5 3CELLCYCLEARREST SENESCENCEAPOPTOSISFigure20-40 Modes of action of thep53 tumor suppressor.The p53 proteinis a cellularstresssensor.In resoonsetohyperproliferativesignals,DNAdamage,hypoxia,and/ortelomereshortening,thep53 levelsin the cellriseand causecellsto undergocellcyclearrest,apoptosis,or(Asdiscussedreplicativecellsenescence.in Chapter17, a senescentcellprogressivelylosesthe abilityto divide.)All of theseoutcomeskeeptumor growthin check.'srossaJddnslounllsol a^eqteql slla)Jo ro^ejur uorl)alasq]rM'saua6Jo ssolP O] pPalosleue) raplosrpleurosoutolqleqf '(t€-02 aln6rl eas)seutosor.llorq)alnuru alqnopluapuedapulserPaddeos pue sn)ol leut6uoIaql urorJpasr)xaeuo)aq-a6elParqpuerlsvNc paredarunq6nolqllo lue^auorleurquo)ale q6nolqtlaqlla-Ieusardo)aldrllnLuaqf roqulnuIdot q6rqeol poljlldLuesraua6aq] q)tqMut sluelnulol pealsnql ;;rmuor6a.rleurosourorq)pal)aJJeaql ur aua6e;o sardo>;osraqurnupeseal)utqllM slla)Jolo^ej uluorl)olaSraqtJnJlltlsuor6a.rpalel;dnpaql Jo saroo)jo raqurnuaql aspal)utue)(apl(rabpuq-uorsn;-abelearqpalle)-osaql) abelearqpue'uorsnJ;enbaunprleurorq)'uolte)!loarlo spunoJpaleadal'pale.raua6uaaqseqalaulolale 6ur1>e1pue uorlerr;dnpe 6ur{let auosouolqle a)uo'uMoqssa)uanoesuo)eqr qllM'aseqd5 sralualla)anrl:a;ep-ggdaqt'abeutepaqt perredarqr;ntl! 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