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Malignant transformation represents thephenotypic end-point of multiple geneticaberrations acting in concert to endow cancercells with a large assortment of biologicalcapabilities1. p53 is a sequence-specific tran-scription factor that stands at the nexus ofsensing and integrating diverse growth andsurvival signals and converting this informa-tion into highly coordinated gene expressionpatterns required to maintain cellular home-ostasis and tumor-free survival of the organ-ism2. Much research effort is devoted todissecting the relative in vivo roles of thedownstream signaling functions of p53 byeither inactivating specific signaling surro-gates (i.e., particular p53 target genes) oraltering p53 itself such that it retains only asubset of its specific activities. On page 63 ofthis issue, Lozano and colleagues use the latterapproach to show the importance of p53 cell-cycle regulation in tumor suppression in vivo.

Liu et al. engineered a Trp53 knock-inmutation in the mouse germ line (515G→C,resulting in the amino acid substitutionR172P), analogous to a human tumor-derivedmutant shown previously to be incompetent inactivating apoptosis yet capable of inducingarrest in the G1 phase of the cell cycle3. Theprobable basis for this selective activity is thatthe mutant protein retains the capacity totransactivate the gene Cdkn1a, encoding the

p21 cyclin-dependent kinase inhibitor, but notapoptotic target genes, such as Bax4 (Fig. 1).Correspondingly, cells derived fromTrp53515C/515C mice were partially competentfor cell cycle arrest but completely defective inapoptosis in response to DNA damage. Withone primary function of p53 compromised,Liu et al. could now assess the requirementand relative contribution of the apoptoticfunction of p53 to tumor suppression in vivo.

In marked contrast to the early-onset thymiclymphoma phenotype of mice completelydeficient in p53 (ref. 5), tumorigenesis wassubstantially delayed in Trp53515C/515C mice,with thymic lymphoma development stronglyinhibited. Moreover, the lymphomas thateventually emerged in Trp53515C/515C micehad notably benign diploid cytogenetic pro-files, in contrast to the aneuploidy present intumors derived from Trp53–/– mice. Thesegenetic data support the view that the cellcycle checkpoint function of p53 and mainte-nance of genomic stability have prominentroles in the suppression of thymic lymphomadevelopment in vivo.

Damned dogma!The prevailing view in the cancer field isthat activation of apoptosis is the dominantmode of tumor suppression by p53. Thisidea results from several different lines ofevidence. First, original reports of micedeficient in p21 indicated that these micehad a compromised G1 arrest response butdid not reproduce the cancer-prone pheno-type of p53-null mice6–8. Second, ectopiccell cycle entry caused by inactivation ofretinoblastoma (Rb) function in the mouseby mutation9 or viral oncoprotein seques-tration10 engenders a p53-dependent apop-totic response. In an extension of this work toa model of epithelial carcinogenesis, viraloncoprotein inactivation of Rb family func-tion provokes a neoplastic phenotype typi-fied by high mitotic index and accompanyingapoptosis that, on a p53-null background,yields a rapidly progressive, apoptosis-resis-tant tumor phenotype. Moreover, by usingmice lacking the proapoptotic protein Bax,this model provided compelling genetic evi-dence that apoptosis contributes substan-tially to tumor suppression11. Third, use of a

Laura D. Attardi is in the Departments ofRadiation Oncology and Genetics, StanfordUniversity School of Medicine, Stanford,California 94305, USA. Ronald A. DePinho is inthe Department of Medical Oncology, Dana-Farber Cancer Institute and the Departments ofMedicine and Genetics, Harvard MedicalSchool, Boston, Massachusetts 02115, USA.e-mail: attardi@stanford.edu orron_depinho@dfci.harvard.edu.

Conquering the complexity of p53Laura D Attardi & Ronald A DePinho

New evidence from a Trp53 ‘knock-in’ mouse model suggests that p53-dependent cell cycle checkpoint controlaccompanied by maintenance of genome stability is important for keeping tumor growth in check.

NATURE GENETICS VOLUME 36 | NUMBER 1 | JANUARY 2004 7

p53 target gene activation

ApoptosisG1 arrest

Tumor Supression

RIP

HypoxiaHyperproliferative

signals

p53

Bax, Puma, Noxa, Perp

p21, other

DNA damage, telomere

dysfunction

STOP

Figure 1 A number of cellular stresses, includingDNA damage, hypoxia and hyperproliferativesignals, activate p53 to stimulate target geneexpression. p53 induces genes encoding p21 andsome other proteins to implement a G1 arrestresponse and genes encoding Bax, Puma, Noxaand Perp to activate the apoptotic pathway. Theparticular downstream pathway activated by p53is influenced by cellular context, and bothpathways contribute to tumor suppression.

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“White meat or dark?” is a familiar questionasked around holiday tables. But what exactlymakes meat white or dark? Dark meat, com-posed primarily of slow twitch muscle fibers,is specialized for extended exertions (stand-ing, walking, slow swimming) and gets the

consistent energy it needs from its high myo-globin content. By contrast, fast muscle, themain component of white meat, fuels quickbursts (sprinting, short flights) and containsless myoglobin.

Because chickens and turkeys stand orroam about and rarely fly, their leg meat isdark while their breast and wing meat iswhite. Conversely, wild birds, such as ducks,which frequently fly, have dark breast andwing meat. As your holiday guests feast ontheir turkey, this may be enough information

for them. But for authors Philip Ingham,Sudipto Roy and colleagues, the question ofwhite meat or dark led to a fascinating investi-gation into how slow and fast muscle is estab-lished during zebrafish embryogenesis and tothe identification of a genetic switch responsi-ble for determining muscle fiber fate1.

Instructive cuesIn the vertebrate embryo, skeletal muscle arisesfrom somites, segmented blocks of mesodermlying on either side of the notochord and

Ava E. Brent and Clifford J. Tabin are in theDepartment of Genetics, Harvard MedicalSchool, 77 Avenue Louis Pasteur, Boston,Massachusetts 02115, USA.e-mail: tabin@genetics.med.harvard.edu

White meat or dark?Ava E Brent & Clifford J Tabin

In zebrafish, slow twitch muscle is specified from a somitic muscle precursor pool by local Hedgehog (Hh) signals. Anew study identifies the transcription factor Blimp-1 as a key downstream mediator in this process.

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mouse model of Myc-induced B-cell lym-phomagenesis showed that kinetics of Myc-induced lymphoma in mice defective inspecific components of the apoptotic path-way, such as caspase-9, are indistinguishablefrom those observed in the absence of p53(ref. 12). The conclusions drawn from thesestudies have been bolstered by the existenceof human tumor-derived p53 mutants com-promised in apoptosis but not arrest func-tion—arguing for the crucial importance ofinactivating apoptotic functions during thecourse of human tumorigenesis.

Both cell cycle regulation and the inductionof apoptosis are fundamental to the action ofp53 in the mouse. Which activity is more rele-vant is probably context-dependent, with cellcycle regulation seeming to be key in thymo-cytes and apoptosis prevailing in other celltypes, such as B cells. One prediction fromLiu et al. is that mice deficient in p53 apop-totic target genes would not be prone tothymic lymphoma. The concept that apop-totic deficiency is not sufficient for thymiclymphomagenesis represents a change fromprevious thinking; because thymocytesundergo a clear p53-dependent apoptoticresponse on DNA damage13, there is a long-standing belief that the predisposition of p53-deficient mice to thymic lymphoma resultsfrom defects in this apoptotic program.

These studies also raise the question ofwhy Cdkn1a–/– mice, which have a compro-mised G1 arrest response, are not prone tothymic lymphoma. This condition may relateto the fact that p21-deficient cells are onlypartially defective in the G1 arrest checkpoint,

and that the activity of another, unknownp53-regulated cell cycle arrest target gene canprovide sufficient cell cycle regulation to pre-vent the malignant transformation of thymo-cytes. Another, not mutually exclusive,explanation for limited tumorigenesis inCdkn1a–/– mice is developmental or somaticcompensation by functionally related cyclin-dependent kinase inhibitors, similar to whathas been described recently for the Rb family14.

Vive la différenceAmong the remaining issues is the questionof what triggers p53 activation to preventthymic lymphoma development. p53 is acti-vated by any of a number of stresses, includ-ing DNA damage, hyperproliferative signalsand hypoxia. The signals that trigger p53activation and, by extension, the down-stream pathway activated by p53 may be fun-damentally different in mice and humans.For example, unlike mouse cells, which havevery long telomeres, human cells have rela-tively short telomeres and therefore suffersevere consequences on telomere attrition.Telomere-based crisis, in which criticallyshort telomeres result in breakage-fusion-bridge cycles, is accompanied by p53 activa-tion and a prominent apoptotic response inmany human cell types15. In certain humancell types, there may be a strong selectionpressure specifically against the apoptoticfunction of p53, which could explain howhuman tumor mutants in which the apop-totic function has been inactivated mighthave arisen. A prediction of this idea wouldbe that the Trp53515C allele in the context of

telomere-based crisis would render micevery cancer-prone in certain compartments,a hypothesis that is now testable through theuse of telomerase-deficient Trp53515C/515C

compound mutant mice. p53 itself is a difficult target for cancer ther-

apy given its active role in promoting agingwhen inappropriately activated. Consequently,depending on the tumor type, it may be mostproductive to selectively target only a specificaspect of p53 function to mollify acceleratedaging in normal tissues, particularly in the set-ting of conventional therapy. Defining the spe-cific signaling surrogates involved in tumormaintenance is a good first step toward design-ing well-tolerated and effective therapies forthe many cancers related to p53 mutations.

1. Hanahan, D. & Weinberg, R.A. Cell 100, 57–70(2000).

2. Vousden, K.H. & Lu, X. Nat. Rev. Cancer 2, 594–604(2002).

3. Liu, G. et al. Nat. Genet. 36, 63–68 (2004).4. Ludwig, R.L., Bates, S. & Vousden, K.H. Mol. Cell.

Biol. 16, 4952–4960 (1996).5. Attardi, L.D. & Jacks, T. Cell. Mol. Life Sci. 55, 48–63

(1999).6. Brugarolas, J. et al. Nature 377, 552–557 (1995).7. Deng, C., Zhang, P., Harper, J.W., Elledge, S.J. &

Leder, P. Cell 82, 675–684 (1995).8. Martin-Caballero, J., Flores, J.M., Garcia-Palencia, P.

& Serrano, M. Cancer Res. 61, 6234–6238 (2001).9. Morgenbesser, S.D., Williams, B.O., Jacks, T. &

DePinho, R.A. Nature 371, 72–74 (1994).10. Symonds, H. et al. Cell 78, 703–711 (1994).11. Yin, C., Knudson, C.M., Korsmeyer, S.J. & Van Dyke,

T. Nature 385, 637–640 (1997).12. Schmitt, C.A. et al. Cancer Cell 1, 289–298 (2002).13. Lowe, S.W., Schmitt, E.M., Smith, S.W., Osborne,

B.A. & Jacks, T. Nature 362, 847–849 (1993).14. Sage, J., Miller, A.L., Perez-Mancera, P.A., Wysocki,

J.M. & Jacks, T. Nature 424, 223–228 (2003).15. Chin, L. et al. Cell 97, 527–538 (1999).

8 VOLUME 36 | NUMBER 1 | JANUARY 2004 NATURE GENETICS

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