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Deconstructing p53 transcriptional
networks in tumor suppression
Kathryn T. Bieging1 and Laura D. Attardi1,2
1 Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, USA
2 Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA

p53 is a pivotal tumor suppressor that induces apopto-sis, stabilization and activation of p53 [1]. p53 also responds to acute
cell-cycle arrest and senescence in response to stress DNA damage signals by inducing apoptosis or cell-cycle arrest to
signals. Although p53 transcriptional activation is im-portant prevent the genomic instability and increased risk for
for these responses, the mechanisms underlying tumor carcinogenesis associated with propaga-tion of damaged cells [3].
suppression have been elusive. To date, no single or As with the response to oncogenic signaling, the response of p53
compound mouse knockout of specific p53 target genes to DNA damage may also have a role in tumor suppression
has recapitulated the dramatic tumor predisposi-tion that because nascent human and mouse tumors display activation of
characterizes p53-null mice. Recently, however, analysis of DNA damage pathway components, including p53 (Box 2) [4].
knock-in mice expressing p53 transactivation domain Studies using mouse lymphoma and fibrosarcoma models,
mutants has revealed a group of primarily novel direct p53 howev-er, suggest that p53-mediated responses to acute DNA
target genes that may mediate tumor sup-pression in vivo. damage are dispensable for tumor suppression, instead
We present here an overview of well-known p53 target highlighting the importance of Arf in p53-mediated tumor
genes and the tumor phenotypes of the cognate knockout suppression [5–7]. Whether the molecular trigger for p53-
mice, and address the recent identification of new p53 mediated tumor suppression is oncogene signaling through Arf or
transcriptional targets and how they enhance our DNA damage is an area of active debate and investigation, and
understanding of p53 transcrip-tional networks central for both are likely to be important (Box 2). Defining the triggers for
tumor suppression. p53 activation in tumor suppres-sion in different settings will be
key to elaborating fully the functional p53 tumor-suppressor
p53: complexity at a molecular and network scale network.
p53 has been studied extensively owing to its paramount
importance in tumor suppression. The significance of p53 in The best-characterized molecular function of p53 in driving
tumor suppression in humans is highlighted by its inactivation in apoptosis, cell-cycle arrest, or senescence is as a transcriptional
over half of all human cancers and by the dramatic cancer activator, although p53 has other biochem-ical activities
predisposition of individuals with Li–Fraumeni syndrome, who including the ability to repress transcription and to promote
inherit a mutant p53 allele. In addition, mice deficient for p53 apoptosis through direct interaction with apoptotic regulators in
develop cancer with 100% penetrance [1,2]. Although we have the cytosol [1,2]. In common with most transcription factors, p53
some under-standing of the molecular mechanisms by which p53 contains distinct domains responsible for sequence-specific DNA
func-tions in tumor suppression, it is increasingly evident that our binding and tran-scriptional activation. The DNA-binding domain
current knowledge is incomplete. The discovery of vast and comprises residues 100–300 and directs p53 to p53-response
varied transcriptional targets controlled by p53 raises new elements (p53 RE). The DNA-binding domain is the most
questions about how these networks coordinate to promote tumor common site for mutations in cancer [8], underscoring the impor-
suppression. Mouse models have been instrumental in beginning tance of p53 DNA-binding function for tumor suppression. Two
to decipher the networks through which p53 functions in vivo, distinct transcriptional activation domains (TADs), spanning
and the insights gained from these studies are the subject of this residues 1–40 and 40–83, cooperate for full p53 transactivation
review. capacity (Figure 2). These domains were defined initially by their
ability to confer activation poten-tial on a Gal4 DNA-binding
p53 plays a fundamental role in the response to cellular stress, domain in reporter assays, and residues within these domains
which can, at least in part, explain its tumor-suppression function crucial for transactivation were pinpointed through additional
(Figure 1). For example, p53 responds to hyperproliferative reporter assays [9–11]. Although both TADs are present in full-
signals caused by oncogene expression by inducing apoptosis or length p53, an amino-terminally truncated form of p53 lacking
cellular senescence as safeguards against tumorigenesis (Box 1). the first TAD, DN40, generated either through alternative
In the absence of cellular stress, p53 is bound by its negative splicing or translational initiation, has been described [12]. Apart
regulator, Mdm2, an E3 ubiquitin ligase that promotes its from the observation that DN40 p53 can cause premature aging
degrada-tion. Oncogene activation can trigger expression of Arf, in mice when overexpressed [13], there has been very limited
which disrupts the p53–Mdm2 interaction, leading to insight into the respective roles of the two TADs gleaned from
cell culture studies. Recently, however, the

Corresponding author: Attardi, L.D. (

0962-8924/$ – see front matter 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tcb.2011.10.006 Trends in Cell Biology, February 2012, Vol. 22, No. 2 97

The pivotal effector functions. in Em–Myc transgenic apoptosis in lymphomas and senescence in sarcomas [88]. and discussion reveals that we are just beginning to scratch the genome-wide chromatin immunoprecipitation (ChIP) studies surface in terms of understanding the tran-scriptional circuitry have revealed that p53 binds to thousands of genes [17]. 98 . 2 DNA Oncogene Nutrient Hypoxia damage expression deprivation Ribosomal dysfunction Oxidative stress Telomere attrition p53 G1 M Metabolism Senescence Angiogenesis G2 S Cell-cycle Apoptosis arrest DNA repair Autophagy Migration Tumor suppression TRENDS in Cell Biology Figure 1. Box 1. including DNA repair. specific contributions of each domain to various p53 func-tions in suppression. In the presence of p53. The ability of p53 to trigger tumor-derived p53 mutant that promotes cell-cycle arrest but not apoptosis and cell-cycle arrest in response to DNA damage and apoptosis – are significantly more cancer-resistant than p53-null mice oncogene activation suggests obvious cellular mechanisms for tumor [75]. In this review we discuss current knowledge of the Mouse models have demonstrated the importance of p53 p53 transcriptional networks involved in tumor apoptotic function in tumor suppression (Box 1) [18]. tumors grow slowly and are suppression is probably cell-type-specific. and mouse models confirm roles for both of these inhibits spontaneous tumorigenesis through senescence [85]. and p53 can respond by either positively or negatively regulating many cellular processes that could contribute to tumor suppression. tumor suppression but also underscores the utility of mouse models for Knock-in mice expressing p53R172P (also termed Trp53515C) – a studying tumor suppression in vivo [83]. Review Trends in Cell Biology February 2012. The question mice. p53 responds to a plethora of stress signals and regulates diverse responses. and we now appreciate that the TADs are identified because of their robust induction in re-sponse to DNA differentially required for the activation of distinct sets of p53 damage signals. In addition. Mouse models reveal key roles for apoptosis and cell-cycle arrest in p53-mediated tumor suppression The discovery that p53-null mice are highly susceptible to spontaneous development [18].16]. Vol. apoptosis is which restoration of p53 function in p53-deficient tumors triggered minimal and tumors grow rapidly [84]. 22. Mouse models have also shown that p53-dependent tumors not only provides compelling evidence of the importance of p53 in growth arrest and senescence contribute to its role in tumor suppres-sion. We then describe a new discussed below). in telomerase-deficient mice. specifically highlighting the have been proposed to explain the context dependence of these importance of p53-mediated apoptosis in suppressing cancer responses. employed by p53 in suppressing can-cer development. functions and roles in tumor suppression. and describe what is known about their cellular target genes and for different biological functions ([14. metabolism and cell mi-gration. disruption of apoptosis through of how p53 drives different responses in different settings is of great expression of Bcl-2 or dominant negative caspase 9 confers a tumor interest. Myriad stress signals can activate p53. activated BRAF [86] and Pten loss. Our p53 directly regulates more than 125 gene targets [2. We highlight those p53 target genes most vivo have been clarified through the generation of TAD mutant thoroughly studied in mouse tumor models. but without p53. some are im-plicated in other cellular processes in which p53 is also involved. which could also Elucidating the functions of p53 target genes in vivo contribute to tumor suppression Revealing in vivo roles of p53 apoptosis target genes [1] (Figure 1). The relative T121.15]. which augments our understanding of suppression. the networks involved in p53-mediated tumor suppression. and numerous mechanisms implicating various cofactors for p53 growth advantage similar to p53 loss. The first evidence of the importance of apoptosis in role of senescence in p53-mediated tumor suppression was further p53-mediated tumor suppression in vivo came from a mouse model of demonstrated in mouse lung and prostate cancer models driven by brain cancer driven by expression of an SV40 large T-antigen mutant. respectively [87]. which inactivates the retinoblastoma (Rb) family of tumor importance of p53-induced apoptosis and senescence in tumor suppressors. as illustrated by studies in characterized by high levels of apoptosis. No. a model for B-cell lymphoma. Furthermore. many of which were knock-in mice. expression of p53R172P suppression by p53. This knowledge can now be harnessed to map tumor-suppression-associated transcriptional program identified the transcriptional networks crucial for p53 function in tumor by dissection of p53 TADs. Although some p53 targets have clear links to p53 functions in apoptosis and cell-cycle arrest.

77] suggests not only that full transactivation is transcription of genes encoding death receptors and ligands. Bax alone does not lead 99 . p53 can engage the intrinsic in response to acute DNA damage [14. including Puma and Noxa. such dispensable for tumor suppression. a DNA-binding domain. Further experimentation will determine whether the damage-induced apoptosis in neurons [19–21] and oncogene- mechanisms of p53 action downstream of acute and chronic DNA expressing mouse embryo fibroblasts (MEFs) [22]. bind is supported by recent studies of knock-in mice expressing a p53 TAD1 directly to Bax and Bak. fibrosarcoma. Box 2. TAF9. Killer/DR5. resulting in membrane mouse precancerous lesions [4]. Studies in mouse lymphoma and permeabilization (MOMP) and release of cytochrome c. No. the ability of Noxa. p5325. This notion family members. 2 Proline TAD1 TAD2 rich DNA binding domain Tet Basic domain domain region 25. DNA damage are not required for tumor suppression in various settings. TFIIH. and the FF residues mutated in the p5353. The LW residues mutated in the p5325. The domain organization of p53 includes two N-terminal transcriptional activation domains (TADs). including Bcl-2. and Pidd. with the asterisks indicating the location of the mutations in the TAD mutant knock-in strains. Pro-apoptotic ultimately impinges upon p53 to promote a tumor-suppressive Bcl-2 effector proteins such as Bax and Bak oligomerize at the response. The replication-fork collapse. These different observations may be reconciled by invoking the possibility that DNA damage induced in incipient tumors is a low- level stress that provokes a mechanistically distinct pathway from the Bax is one of the earliest-studied p53 transcriptional targets.Human ---MEEPQSDPSVEPPLSQETFSD LWKLLPENNVLSPLPS-QAMDDLMLSPDDIEQWFTEDPGP p300 CBP GCN5 TAF9 TFIIH TAF6 TBP TRAP80 TRENDS in Cell Biology Figure 2. including the transcriptional regulator proteins TAF6. intrinsic apoptotic pathway is reg-ulated by the ratio of pro- and the activation of ATM and ATR kinases. This model provides an explanation of how both thymocytes or intestinal crypt cells [23. Vol. a tetramerization (Tet) domain. inhibiting MOMP. BH3 (Bcl-2 mutant. liberating such as Puma and p21. a proline-rich domain. The failure of the p5325. By contrast.26 mutant and genetic experiments revealed its importance for DNA may selectively respond to chronic. The model is supported by evidence of markers for DNA- damage pathway activation.26.54 knock-in mouse correspond to amino acids 53 and 54 in both mouse and human p53 (marked in red). Bcl-XL. fibrosarcoma models. and p53 participates in this pathway by inducing the B cell lymphoma [15. Although Bax- the oncogene-Arf and DNA-damage signaling pathways could be deficient mice are characterized by lymphoid hyperplasia. The pro-survival Bcl-2 suppression requires oncogene-triggered induction of the Arf tumor suppressor but not the acute DNA damage response [5–7]. DNA damage responses in p53-mediated tumor Investigating p53 apoptotic target genes may therefore be suppression important for understanding the molecular mechanisms of p53- mediated tumor suppression. The sequence alignment of the TADs of mouse and human p53 is shown. and histone acetyltransferases p300. however.26 knock-in mouse strain correspond to amino acids 25 and 26 in mouse p53 and 22 and 23 in human p53.54 ** ** Mouse MTAMEESQSDISLELPLSQETFSG LWKLLPPEDILP---SPHCMDDLLLP-QDVEEFFEGPS-. It is possible that the p5325. A model has intrinsic or extrinsic signaling pathways. a component of the human STAGA [STP3–TAF(II)31–GCN5–L acetylase] complex.26 to suppress tumor formation in vivo in mouse models of engagement of transmembrane death-domain proteins at the cell diverse cancers including NSCLC. This cascade then apoptotic to pro-survival Bcl-2 family members. classical p53 target genes essential for apoptosis and cell-cycle arrest. Transactivation domains mediate interactions between p53 and cofactors. acute DNA damage response [4]. and GCN5. TRAP80.15].26 53. and surface. and to mediate cell-cycle arrest and apoptosis Bax and Bak to promote apoptosis. Please note that the exact boundaries of the interaction sites are not precise. which converge at the been proposed whereby oncogene-induced proliferation triggers level of caspase activation but differ in upstream stimuli. supports the notion that robust transactivation of these target genes is required for p53 effector cell death pathway through the induction of Bax. the formation of double-strand DNA breaks. and Mcl-1. perturb these interactions.26 mutant to efficiently activate homology domain 3)-only pro-apoptotic Bcl-2 family members. 22. the extrinsic apoptotic pathway is activated by p5325. low-level DNA damage but not acute DNA damage. Puma and functions downstream of acute DNA damage. and a basic region. suggest that p53-mediated tumor eventually activating effector caspases. but also that p53 responses to acute as Fas. However. loss of important for tumor suppression. including p53 activation. Review Trends in Cell Biology February 2012. TBP. but not in damage are distinct. in human and mitochondrial outer membrane. CBP. A variety of protein cofactors that regulate chromatin remodeling and/or transcriptional initiation interact with p53 via one or both TADs. medulloblastoma.24]. p53 can trigger apopto-sis via the The role for the DNA damage response in triggering p53 tumor- suppressor function has been a topic of some debate.

89] effector related and keratinocytes after DNA damage cell carcinomas to PMP-22 Apoptosis competent: Oncogene-expressing MEFs after DNA damage Tnfrsf10b Apoptosis deficient: No spontaneous tumors Enhanced tumorigenesis: (Dr5. intestinal crypt by Em–Myc -acetate-induced cells. cortex and LPV–SV40 T121 antigen hippocampus) and Mammary tumors driven oncogene-expressing MEFs by C3(1)-SV40 Large T antigen after DNA damage B cell lymphomas driven Choroid plexus cells by Em–Myc expressing T Pancreatic b cell tumors 121 driven by pIns-MycERTAM Apoptosis competent: Intestinal crypt cells. 22.43] component 3 external granule layer. Vol. Postnatal lethality UVB-induced skin squamous [47. B cell lymphomas driven [34. 2 Table 1. No.24–29] X protein external granule layer. Killer.36. apoptosis) intestinal crypt cells. Phenotypes of p53 apoptosis target-gene mouse knockout strains Target gene p53-dependent apoptotic phenotype Knockout mouse Knockout mouse tumor models Refs of null cells phenotype Bax Apoptosis deficient: No spontaneous tumors Enhanced tumorigenesis: Bcl-2-associated Neurons (of the dentate gyrus. ovary protein with a cells and intestinal cells after death domain DNA damage 100 .90] factor receptor lymphadenopathy) and of Apc superfamily liver hyperplasia member 6 Decreased tumorigenesis: Ovarian cancers driven by combined oncogenic Kras expression and Pten loss Hepatocellular carcinomas induced by DEN treatment Pidd Apoptosis competent: No spontaneous tumors Not determined [51] p53-induced Thymocytes. splenocytes. embryonic neurons. Colon cancers driven by loss [52–54.Review Trends in Cell Biology February 2012. Oncogene-expressing MEFs and B cell lymphomas driven [49. Apoptosis competent: member 10b Cells of stomach and proximal (Death receptor 5) colon after DNA damage Tnfsf6 (Fas. Brain tumors driven by [19–22. CD95) Apoptosis competent: Increased lymphocyte Enhanced tumorigenesis: tumor necrosis Thymocytes after DNA damage numbers (splenomegaly.50] TRAIL-R2) cells of the brain. pro-B/pre-B cells and oncogene-expressing MEFs after DNA damage Primary myeloid progenitors expressing Myc Apoptosis competent: Keratinocytes after DNA damage Pmaip (Noxa) Apoptosis deficient: No spontaneous tumors No effect: Phorbol-12 Neural precursor cells. thymocytes and retinal cells after DNA damage Bbc3 (Puma) Apoptosis deficient: No spontaneous tumors Enhanced tumorigenesis: Bcl-2 binding Neurons (of the dentate gyrus.43] -myristate-13 keratinocytes. retina by Em–Myc (p53 up regulated and subventricular zone of the modulator of lateral ventricle).48. B cell lymphomas driven [33–38. and oncogene-expressing protein 1 MEFs after DNA damage Apoptosis competent: Thymocytes and Pro-B/pre-B cells after DNA damage Perp Apoptosis deficient: Epithelial blistering Enhanced tumorigenesis: p53 apoptosis Thymocytes. thymocytes. spleen and by Em–Myc Tumor necrosis thymus after DNA damage Hepatocellular carcinomas factor receptor induced by DEN treatment superfamily.

that are essential advanced than in controls. in keratinocytes Em–Myc [26–29] (Table 1). Puma deficiency accelerates tumorigenesis in the mouse models demonstrate roles for many of these genes in context of oncogene activation in the Em–Myc lymphoma model tumor suppression. spontane-ous tumor development [33. Em–Myc/Noxa / nullizygosity promotes some aspect of tumorigenesis.34]. which contrasts with the ability of Puma to bind all pro-survival Bcl-2 family members equivalently [39]. Mice deficient for the [33–35]. however.58]. Other p53 target genes involved in senescence and cell-cycle apoptotic function(s). and cell-cycle arrest. respectively [31. Noxa and Puma gene amplification. apoptosis and tumor suppression in vivo. p21 is important for the tumorigenesis G1 checkpoint response because p21 loss compromises p53- [34] and that Noxa deficiency fails to accelerate lympho.25]. Although initial a few exceptions. indicat-ing that Perp loss promotes mediators of the apoptotic arm of the p53 pathway.56]. levels of apoptosis in most cell types from reports suggested that p21-null mice do not display an enhanced tumor predisposition [57. Perp-deficient mice The p53 target genes Pmaip1 and Bbc3 encode the BH3-only developed tumors with reduced latency. Thus. explain full p53 function. Puma both tumor initiation and progression [48]. brain and encodes a tetraspan membrane protein that localizes to pancreatic b cell cancer. contribute to p53-mediated tumor arrest also demonstrate context-specific tumor-sup-pressor suppression in this model. and this may be explained by its specific affinity for Mcl1. Perp tumorigenesis in mouse models of mammary. mediated G1 arrest in response to DNA damage [57. suggesting that other target genes.Review Trends in Cell Biology February 2012. 22. suggesting that are induced by p53 to similar levels in the contexts of apoptosis Gadd45a is crucial for maintenance of genomic stability by p53. Because Perp of p53. whereas Bax.34]. Collec-tively.58]. Myc/Puma / mice. To understand fully the role of p53 transactivation in tumor suppression we must also consider those Noxa displays more limited pro-apoptotic potential than p53 targets that promote cell-cycle arrest and senescence. but far from mirror the phenotype of also insufficient to initiate tumor formation p53-null mice [57].40–42]. deficiency nearly or completely abolishes DNA-damage-induced. these studies suggest that p21 deficiency can enable tumorigen-esis in select settings. In most but not all cancer models driven by because no spontaneous tumors are observed in double chemical carcinogens. Additional mouse studies have queried the role of the extrinsic Given the crucial role of Puma in apoptosis in diverse cell types apoptotic pathway in p53 function in vivo. intercellular adhesion junctions. that may not be phenotypes in chemical and genetic mouse cancer models (Table relevant for p53 action in tumor suppression. p53 protein interacts directly with pro-apoptotic and/or / mice display dramat-ic lethal blistering in the epidermis and pro-survival Bcl2 family mem-bers to induce MOMP [30]. other stratified epithelia. undergoing Puma in p53-mediated apoptosis. In a mouse model of squamous cell suppression may not reflect an exclusive role as a transcriptional carcinoma (SCC) in which mice lacking Perp in the epider-mis target. In the context of gene Perp is upregulated to higher levels during p53-mediated oncogene activation. and tumors were more proteins Noxa and Puma. however. No. as with 1) [49–54]. Because Noxa deficiency senescence target genes compromises apopto-sis less than Puma loss. Further-more. as well as in B-cell lymphoma driven by desmosomes. and therefore do not specify the apoptotic Although Gadd45a deficiency alone does not predispose mice to cell fate [40. such as acute DNA damage. It is noteworthy that Bax also [47]. apoptosis compared to cell-cycle arrest. Loss of both Noxa and Puma is compared to controls [60]. Vol. similar to p53 / MEFs [65]. a subsequent study suggested a Noxa / Puma / mice are indistinguishable from those in Puma / slightly accelerated mean latency of spontaneous tumor onset mice after various stimuli [43]. A specific requirement for Noxa in DNA damage-induced apoptosis is seen in particular Revealing the in vivo roles of p53 cell-cycle arrest and cell types (Table 1) [34. it is surprising that Puma / mice are not prone to p53 target genes Dr5 (also known as Killer and Trail receptor 2). However. Perp suppressor activity because Bax deficiency acceler-ates overexpression is sufficient to induce apoptosis [46]. Gadd45a is a p53 target gene with a Mapping the p53 networks involved in tumor suppres-sion can demonstrated role in controlling G2/M progression. irradiation or oncogene expression. activity (Table 2). it is not surprising The cyclin-dependent kinase inhibitor p21 (Cdkn1a) was the first that Noxa / mice are not predisposed to spontaneous p53 target gene to be identified [55. studies of p53 apoptosis target genes in Bax loss. suggesting that it is a central p53 apoptosis mediator (Table 1). including aneuploidy and cellular responses. With senescence similarly to wild-type MEFs [59]. Gadd45a / be informed by identifying target genes selective to specific MEFs display chromosomal defects. p21 / MEFs are not immortal.32]. including Puma / mice develop tumors with similar kinetics to Em– tumor initiation.45]. Analysis of Perp in mouse models has uncovered roles in participates in a transcription-independent pro-apoptotic function adhesion. possibly those with non. This finding may be Pidd (p53-induced death domain) and Fas/CD95 are not prone to explained by Puma playing a role primarily downstream of potent developing spontaneous tumors and have variable tumor stress signals. 2 to tumor development in mouse models [24. Moreover. Analysis of mice deficient for both Puma and Noxa has reinforced the dominant role for p53 / MEFs. Bax does display tumor. Unlike magenesis in the Em–Myc model [36]. p21 homozygous mutant mice [43]. pro-gression or metastasis (Table 2) [61–64]. suggesting a minimal role for Noxa in tumor Collectively. the p53 target spontaneous tumor 101 . p53-dependent apoptosis in a vari-ety of cell types [33. Interestingly.44. were exposed to chronic UVB radiation [48]. suppression [36]. Importantly. tumorigene-sis in Em–Myc/Puma / mice is substantially delayed rel-ative to Em–Myc/p53+/ mice [36]. Puma. although their roles are not sufficient to [36–38]. tumor studies have relied on conditional the requirement for Bax in p53-dependent apoptosis and tumor knock-out strategies [47].

Mice genes for tumor suppression in vivo in specific settings. Exactly how Ptprv functions in tumor suppression remains un-clear. loss of Gadd45a both accelerates arrest. It is also possible loss can promote tumorigenesis in specific models [72. In fact. p53 R172P/ R172P/p21 knockout mice do not display any spontaneous tumor phenotype. In fact. No. mice exhibit increased carcinogenesis follow-ing hyperproliferative signals or DNA damage. the p53-inducible Ptprv gene encodes a transmem-brane effector functions. potentially involved in different p53 nally. thyroid tumors. 2 Table 2. the striking tumor predisposition of p53-null mice might cell-cycle arrest responses to acute DNA damage. that multiple gene products. but are highly susceptible to deter-mine clearly whether p53 activation of a given gene is infection. / mice develop tumors with shorter latency than either although loss of these targets can contribute to tumor p53R172P/R172P or p21 / mice [76]. DNA repair and other cellular processes. DNA damage receptor type. collaborate in tumor suppression and that. Pml important for p53 tumor-suppressor activity. confounding tumor analyses [72]. In the target genes have p53-independent functions in apoptosis. 22. Pml is a direct p53 target gene unrelated to their roles as direct effectors of p53 function. were employed [75]. Vol. but functions. Collaborating p53 functions in tumor suppression To address the importance of the concerted action of dif- ferent p53 cellular functions in tumor suppression.62–64.73].Review Trends in Cell Biology February 2012. Fi. which can activate p21 – the analysis of individual p53 transcriptional targets through the major cell-cycle regulator transcriptionally activated by p53 – mouse knockout strategies has revealed the importance of these but not apoptosis target genes (Box 1).68]. Ptprv / mice do be explained by combined loss of several key p53 effector not develop spontaneous tumors within the first year of life. many of these the apoptotic pathway in tumor suppression. after oncogene expression Skin carcinomas after UV irradiation inducible 45 alpha Cell-cycle arrest of Breast cancers driven by MMTV–v-Ras keratinocytes after DNA damage Decreased tumorigenesis: Breast cancers driven by MMTV–Myc Pml Deficient: No spontaneous tumors Enhanced tumorigenesis: [69–73] Promyelocytic Senescence of MEFs after Increased susceptibility Leukemias in cathepsin-G-PML/RARa leukemia oncogene expression to infection transgenic mice Papillomas after DMBA and TPA treatment No effect: MMTV–neu driven breast cancers Ptprv Deficient: No spontaneous tumors Enhanced tumorigenesis: [74] Protein tyrosine G1 arrest of MEFs after (within 1 year) Papillomas after DMBA treatment phosphatase. development in the face of the tumor initiation rates and tumor spectra are similar 102 . Given that many p53 exposure to UV or g-radiation relative to controls [65. mice homozygous for this mutant allele and also null for p21 were deficient for any single target gene fail to recapitulate the generated. and kinase inhibitor 1A Competent: at a mean latency pheochromocytomas driven by Rb+/– Senescence of MEFs after of 16 months Various tumor types after irradiation serial passage Carcinomas after DMBA and TPA Cell-cycle arrest and treatment senescence of MEFs after Intestinal adenocarcinomas in oncogene expression Csnk1a1-null mice No effect: Breast cancers driven by MMTV–v-Ras Gadd45a Deficient: No spontaneous tumors Enhanced tumorigenesis: [65–68. as described next. Nonetheless. Cyclin-dependent G1 cell-cycle arrest of MEFs No tumors in >1 year Renal carcinomas driven by Apc loss 91–94] after DNA damage Spontaneous tumors Pituitary tumors. re-vealing that Gadd45a function is the tumor phenotypes of mice deficient for these genes are highly context-dependent [67. it is possible that and inhibits tumor onset. V development. Although Ptprv / MEFs are deficient in result. growth context of oncogene activation.95] Growth arrest and Cell-cycle arrest of MEFs Thymic lymphomas after g-IR DNA damage. This [69] essential for senescence triggered by oncogenic Ras point can only be unequivocally addressed by generating knock- expression [70. Pml-deficient mice do not exhibit a in mice with mutations in the p53 REs of specific target genes to spontaneous tumor predisposition. mice Perspectives on individual target-gene knockouts Although expressing the p53R172P mutant.66]. do develop more papillomas than wild-type mice after DMBA treatment [74]. as a tyrosine phosphatase [74]. Phenotypes of p53 cell-cycle arrest and senescence target-gene mouse knockout strains Target gene p53-dependent cell-cycle arrest Knockout mouse phenotype Knockout mouse tumor models Refs phenotype of null cells p21 Deficient: Multiple reports: Enhanced tumorigenesis: [57–60.71]. and analysis of these mice demonstrated that p53 uses dramatic and completely penetrant spontaneous tumor phenotype p21 cooperatively with of p53-null mice (Tables 1 and 2).

(Right) Transactivation by either TAD1 or TAD2 allows p53 responses to oncogene activation. but can promote tumor suppression in a number of mouse models.77].53.54 and p53-null samples. despite complete amino acid substitutions within the two p53 TADs were deficiencies in DNA-damage-induced p53-mediated apoptosis generated to dissect the roles of these TADs in various contexts and cell-cycle arrest (A. allows the p5325.26 to promote very low-level activation of various classical p53 target genes may also contribute to tumor suppression. Review Trends in Cell Biology February 2012.54. with L25Q. is unable to activate efficiently the expression of canonical p53 target genes. The tumor-suppressor capability of p5325. Abhd4. 103 . The ‘?’ denotes additional. Mutation of the first that p53-triggered cell-cycle arrest and apoptosis are crucial for TAD (termed p5325. still-unknown genes crucial for responses to acute DNA damage and oncogene activation. p5325.54 p53 p53 p5325. induction of a small subset of p53-depen- dent genes is similar to that seen in wild-type cells [14.26. (a) (Left) Transactivation domain 1 (TAD1) and robust transactivation of classical p53 target genes are required for responses to acute DNA damage. instead. tumor suppression in diverse cell lineages in mouse models independent functions of p53 are required for tumor suppression (Figure 3a) [15. we used gene expression profiling data generated with the p5325. Noxa. we identified genes induced at least twofold and within 1. Furthermore. activation to p53 tumor-suppression function and has identified possibly because of residual activation of particular p53 target novel p53 target genes with probable roles in p53-mediated tumor genes by p53R172P [76]. and recently a new approach utilizing p53 TAD mutant genes is dispensable for tumor suppression. A p53 TAD1 mutant. which all have tumor-suppressor activity. Strasser.26 is also unable to induce apoptosis or cell-cycle arrest in response to acute DNA damage. No. Functional analysis of p53 transactivation domain (TAD) mutants identifies p53 target genes involved in tumor suppression. p5325. Perp and Puma. including p21. Vol. generation of Puma / p21 / mice.54 TAD1 TAD2 TAD1 TAD2 p5353. (b) Comparison of gene expression profiles of p53 wild-type and p53-null HrasV12-MEFs reveals more than 1000 differentially expressed genes. it is un-clear whether these unable to mount responses to acute DNA dam- tumor phenotypes relate to loss of function as direct p53 target age.). 2 in p53R172P/R172P/p21 / and p53 / mice. which activates only a small subset of p53 target genes. including apoptosis and cell-cycle arrest. p5325. Remarkably. To enrich for genes with specific roles in tumor suppression. A similar rationale led to the suppression. either in cell-cycle arrest or apoptosis. For example.26 Analysis of p53 TAD mutant knock-in mice and wild-type p53 represent novel p53 targets. these findings are not incompatible with the notion model of oncogene-induced senescence. although potentially through tran-scriptional results in severely impaired transactivation of nearly all known programs distinct from those delineated under conditions of acute p53-dependent genes. these data indicate that robust cannot be excluded. Puma and Noxa. relative to p5325. Phlda3. knock-in mouse potent transactivation of novel p53 (a) Acute DNA damage Oncogene activation (b) Tumor suppression Lack of tumor suppression wt p53 p5325. etc. As mentioned above. personal communication). Surprisingly. 22. which lack tumor-suppressor activity. p53 has two discrete transcriptional activation of many well-character-ized p53 target TADs. but is capable of genes. these compound Knock-in mice expressing p53 mutants carrying specific mutant mice are not abnormally cancer-prone.26 mutant. with a few p53 target-gene knockout mice have failed to resolve fully the exceptions.26 can be explained by its ability to activate robustly a limited set of novel direct p53 target genes (Sidt2.W26S mutations) tumor suppression.26 can efficiently activate expression of only a limited number of mostly novel target genes. Using transcriptomics analysis of HrasV12-MEFs. although DNA damage. The majority of genes efficiently induced by both p5325. Microarray analysis of HRasV12-MEFs These data suggest that func-tions of p53 other than the responses expressing the different p53 mutants allowed char-acterization of to acute DNA damage may be important in tumor suppression. This limited transactivation capability role of p53 transcriptional activation in tumor suppres-sion. The capacity of p53 25. p53 mutant transcriptional activity in a Importantly. p5325.26 mutant to mediate only Although analysis of these mice has revealed tumor phenotypes particular p53 effector functions [14. but is a potent tumor suppressor.26 and p5353.15].26 p53 null p53 RE p53 RE p53-regulated genes in tumor suppression: 130 genes Puma Phlda3 p21 Bax Genes downregulated in mouse and human cancer Noxa Abhd4 Perp Sidt2 ? ? ? 14 genes: G1 Crip2 Ndrg4 Polk M Def6 Kank3 Ctsf Phlda3 Ttc28 Mgmt S Arap2 Sidt2 Ercc5 G2 Rgs12 Abhd4 Cell cycle arrest Apoptosis Tumor suppression TRENDS in Cell Biology Figure 3. p5325.26. including p21. although strains has helped to address the contribution of transcrip-tional p53R172P/R172P/p21 / mice display longer overall survival. and that.26.53. the pos-sibility that transactivation.15]. including Bax.26.26 is in a very context-dependent manner. This list of 130 genes was then filtered for those commonly downregulated in human and mouse tumors according to the EBI Gene Atlas database. A group of 14 candidate genes with probable roles in p53-mediated tumor suppression was defined by this analysis.5 standard deviations by p53wt. of p53 function.

including cell-cycle regulation. Defining the cofactor binding that of p53-null cells. Beyond unraveling the the signatures derived from analysis of mouse cells were effective mechanisms of p53-mediated tumor suppression. to activate transcription is indeed required for tumor suppression.53.A. but is a functional development.26. our studies are not incompatible with an additional role for p53 at the mitochondrion in tumor suppression. Jeanine Frey and Dadi Jiang for critical reading of the manuscript. Moreover. this mutant is completely cytoskeletal function (Crip2. fundamental for p53 cel-lular responses and tumor suppression. by suggesting strategies to mitigate the migration and DNA repair.26. p53 targets in one mouse. For example. and DNA repair competent to suppress the development of a wide range of tumor (Polk. Stud- tumor suppression (Figure 3b). It has been challenging to expression profiles of cells map the transcriptional effectors of p53 tumor-suppressor expressing p53 variants functional in tumor suppression function because of the subtle tumor phenotypes of single or (p5325. transcription by recruiting cofactors involved in transcriptional initiation and chromatin modification to the transcriptional start References sites of target genes. the list ies of p53 TAD mutant knock-in mice have helped to address this was filtered for genes known to be downregulated in human and point specifically by employing p5325. Collectively.F54S within the second TAD binding protein (TBP) [79]. TAD2 specifically binds to (p5353. C. suggesting that development in diverse contexts. Vol.26. Although p53 is unequivocal-ly involved in tumor suppressor. transcription factor IIH (TFIIH) [80]. These findings not only suggest that the therefore define a new network of p53 targets important for ability of p53 to trigger responses to acute DNA damage is tumor suppres-sion (Figure 3). thereby generating a list of encoded by a host of p53 target genes mediate the tumor- 130 mostly novel p53-dependent genes likely to be impor-tant for suppressor function of p53. therapeutic applications. The tapestry of p53 tumor suppression will be further Acknowledgments illuminated by deciphering the molecular basis for differ-ent We thank Colleen Brady. Biochemical analysis of human p53 suggests 1 Brady. The p5325.54 mutant is specificities of each TAD at different promoters will provide a ineffective in p53 effector function in vitro and in tumor framework for under-standing context-specific p53 responses. Future investigation of these new p53 target tumor-suppressor func-tion. gene have remained surprisingly elusive. 123. demonstrating that the ability of p53 including tumor suppression. For further refine-ment. tumor-suppres-sion-associated target genes and which cellular Importantly. the 130-gene list could be used to predict accurately processes are most crucial for the suppression of cancer the p53 status of human breast cancer samples. p5353. 2 target genes. in association with efficient activation of a small subset of scribed as a direct p53 target involved in apoptosis and frequently novel direct p53 target genes. or both. was previously de.54) alone do not compromise p53 transactiva. Rgs12). J. Ercc5). some with demonstrated tumor- lost in human lung cancers [78]. Arap2). 2527– that TAD1 and TAD2 2532 104 . Included in this list are genes involved in several allowing an effective phenocopy of the knockdown of numer-ous major functional categories: cell signaling (Phlda3. to arrive at a group of 14 candidate tumor ly impaired for activation of the majority of p53 target genes.53.Review Trends in Cell Biology February 2012. Mgmt. minimal transactivation of canonical p53 target differentially interact with some cofactors.77]. but also have important in differ-ent cellular processes. Intriguingly. Notably. mutation of both TADs to interaction with the histone acetyl-transferases (HATs) p300 (p5325. p53 acti-vates not be cited because of space constraints. are important for tumor suppression. it provides a powerful and unique tool to eliciting senescence or apoptosis in response to cellular stress pinpoint those p53 targets most crucial for p53 tumor-suppressor signals. We apologize to authors whose work could TAD requirements at different target genes. These genes represent bona fide suppressor activity. To identify such tumor-suppression target genes.54. these stud-ies have shed light on how p53 target genes because nearly all contain p53 consensus sites. Daniela Kenzelmann Brozˇ.26 mutant is deficient for efficient in tumor suppression is crucial for broadly under-standing cancer transactivation of most but not all p53 targets.54. and Attardi.54) results in a transcriptional profile resem-bling and CBP [81. Given the function of these genes dispensable for tumor suppression. suppression in vivo [15. and both TADs contribute tion capability or biological activity. recruitment of others. One of these. which is severe- mouse cancers.82] (Figure 2). Concluding remarks Deciphering the molecular mechanisms underlying p53 function Because the p5325. No. future analysis of a p53-dependent manner in response to DNA damage or these will contribute to a better understanding of which of the p53 oncogene expres-sion in both mouse and human cells [15]. Phlda3. TAD 1 interacts with TATA Although substitutions of F53Q. Thus. TAD knock-in mice has elucidated a clear distinction in the overexpression and knockdown approaches revealed that several transcriptional programs for p53 responses to acute DNA damage of these genes behave as tumor suppressors. p53 suppresses tumorigenesis by elaborating a new network of are directly bound by wild-type p53 by ChIP. Cell Sci. analysis of the in identifying genes with relevance to human cancer. these studies lay the genes will more clearly unravel their precise roles in tumor groundwork for fully elaborating the intricate circuitry suppression. types. suppressors. leading to the notion that the combined actions of proteins p53-null) [15]. but collaborate in the genes. an observation with p53 mutants defective for tumor suppression (p53 25.26. (2010) p53 at a glance.53. 22. p53wt) were compared with those of cells double p53 target-gene knockout mutant mice. Kank3. and are regulated in potential p53 tumor-suppres-sor mediators. p53-mediated tumor suppres-sion is detrimental p53-dependent side effects resulting from DNA- likely to rely on the coordinate engagement of multiple diverse damaging radiation and che-motherapies while preserving p53 pathways (Figure 1). These analyses and oncogenic signaling.26. L.D. the molecular details of p53 action in tumor suppression activity.

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