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Review

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. (attardi@stanford.edu).

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

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]. 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]. 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. In the presence of p53. employed by p53 in suppressing can-cer development. The relative T121. respectively [87]. activated BRAF [86] and Pten loss. many of which were knock-in mice. metabolism and cell mi-gration. including DNA repair. Although some p53 targets have clear links to p53 functions in apoptosis and cell-cycle arrest. Box 1. Vol. 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]. functions and roles in tumor suppression. specifically highlighting the have been proposed to explain the context dependence of these importance of p53-mediated apoptosis in suppressing cancer responses. 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. apoptosis is which restoration of p53 function in p53-deficient tumors triggered minimal and tumors grow rapidly [84]. and p53 can respond by either positively or negatively regulating many cellular processes that could contribute to tumor suppression. p53 responds to a plethora of stress signals and regulates diverse responses. the networks involved in p53-mediated tumor suppression. specific contributions of each domain to various p53 func-tions in suppression. and numerous mechanisms implicating various cofactors for p53 growth advantage similar to p53 loss. Review Trends in Cell Biology February 2012. 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). 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. tumors grow slowly and are suppression is probably cell-type-specific. in Em–Myc transgenic apoptosis in lymphomas and senescence in sarcomas [88]. 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. but without p53. which augments our understanding of suppression. some are im-plicated in other cellular processes in which p53 is also involved. Our p53 directly regulates more than 125 gene targets [2.15].16]. In addition. Myriad stress signals can activate p53. Furthermore. 98 . 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. in telomerase-deficient mice. No. 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]. which inactivates the retinoblastoma (Rb) family of tumor importance of p53-induced apoptosis and senescence in tumor suppressors. 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. We then describe a new discussed below). 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]. We highlight those p53 target genes most vivo have been clarified through the generation of TAD mutant thoroughly studied in mouse tumor models. as illustrated by studies in characterized by high levels of apoptosis. The pivotal effector functions. 22. expression of p53R172P suppression by p53. The question mice. and describe what is known about their cellular target genes and for different biological functions ([14. and mouse models confirm roles for both of these inhibits spontaneous tumorigenesis through senescence [85]. a model for B-cell lymphoma.

Studies in mouse lymphoma and permeabilization (MOMP) and release of cytochrome c. p5325. a component of the human STAGA [STP3–TAF(II)31–GCN5–L acetylase] complex. the extrinsic apoptotic pathway is activated by p5325. with the asterisks indicating the location of the mutations in the TAD mutant knock-in strains. By contrast. a proline-rich domain. TRAP80.54 ** ** Mouse MTAMEESQSDISLELPLSQETFSG LWKLLPPEDILP---SPHCMDDLLLP-QDVEEFFEGPS-. TAF9. medulloblastoma. but also that p53 responses to acute as Fas. supports the notion that robust transactivation of these target genes is required for p53 effector cell death pathway through the induction of Bax. in human and mitochondrial outer membrane. bind is supported by recent studies of knock-in mice expressing a p53 TAD1 directly to Bax and Bak. acute DNA damage response [4].Human ---MEEPQSDPSVEPPLSQETFSD LWKLLPENNVLSPLPS-QAMDDLMLSPDDIEQWFTEDPGP p300 CBP GCN5 TAF9 TFIIH TAF6 TBP TRAP80 TRENDS in Cell Biology Figure 2.26 to suppress tumor formation in vivo in mouse models of engagement of transmembrane death-domain proteins at the cell diverse cancers including NSCLC. The model is supported by evidence of markers for DNA- damage pathway activation. Bcl-XL. CBP. low-level DNA damage but not acute DNA damage. and surface.26. This model provides an explanation of how both thymocytes or intestinal crypt cells [23. a tetramerization (Tet) domain. 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. 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. p53 can engage the intrinsic in response to acute DNA damage [14. such dispensable for tumor suppression. resulting in membrane mouse precancerous lesions [4]. and Pidd. Bax alone does not lead 99 . It is possible that the p5325.26 mutant to efficiently activate homology domain 3)-only pro-apoptotic Bcl-2 family members. No. TFIIH.24]. classical p53 target genes essential for apoptosis and cell-cycle arrest. The sequence alignment of the TADs of mouse and human p53 is shown. The LW residues mutated in the p5325. which converge at the been proposed whereby oncogene-induced proliferation triggers level of caspase activation but differ in upstream stimuli. a DNA-binding domain. Please note that the exact boundaries of the interaction sites are not precise. The replication-fork collapse. 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]. A model has intrinsic or extrinsic signaling pathways. 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. and p53 participates in this pathway by inducing the B cell lymphoma [15. TBP.26 53. but not in damage are distinct.26 knock-in mouse strain correspond to amino acids 25 and 26 in mouse p53 and 22 and 23 in human p53. intrinsic apoptotic pathway is reg-ulated by the ratio of pro- and the activation of ATM and ATR kinases. and the FF residues mutated in the p5353.54 knock-in mouse correspond to amino acids 53 and 54 in both mouse and human p53 (marked in red). fibrosarcoma models. Puma and functions downstream of acute DNA damage. including p53 activation. The pro-survival Bcl-2 suppression requires oncogene-triggered induction of the Arf tumor suppressor but not the acute DNA damage response [5–7]. 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 formation of double-strand DNA breaks. DNA damage are not required for tumor suppression in various settings. loss of important for tumor suppression. and histone acetyltransferases p300. including Bcl-2. BH3 (Bcl-2 mutant. and GCN5. Transactivation domains mediate interactions between p53 and cofactors. This notion family members. The domain organization of p53 includes two N-terminal transcriptional activation domains (TADs). A variety of protein cofactors that regulate chromatin remodeling and/or transcriptional initiation interact with p53 via one or both TADs. Although Bax- the oncogene-Arf and DNA-damage signaling pathways could be deficient mice are characterized by lymphoid hyperplasia.77] suggests not only that full transactivation is transcription of genes encoding death receptors and ligands. Killer/DR5. 22. however. Vol. the ability of Noxa. and to mediate cell-cycle arrest and apoptosis Bax and Bak to promote apoptosis. fibrosarcoma. 2 Proline TAD1 TAD2 rich DNA binding domain Tet Basic domain domain region 25. This cascade then apoptotic to pro-survival Bcl-2 family members. Box 2.26 mutant and genetic experiments revealed its importance for DNA may selectively respond to chronic. perturb these interactions. liberating such as Puma and p21. and Mcl-1. including Puma and Noxa. The failure of the p5325. including the transcriptional regulator proteins TAF6. Review Trends in Cell Biology February 2012. inhibiting MOMP.15]. and a basic region. suggest that p53-mediated tumor eventually activating effector caspases. However.

spleen and by Em–Myc Tumor necrosis thymus after DNA damage Hepatocellular carcinomas factor receptor induced by DEN treatment superfamily. No. 2 Table 1. Apoptosis competent: member 10b Cells of stomach and proximal (Death receptor 5) colon after DNA damage Tnfsf6 (Fas. thymocytes. Colon cancers driven by loss [52–54.48. embryonic neurons. apoptosis) intestinal crypt cells.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.Review Trends in Cell Biology February 2012. Postnatal lethality UVB-induced skin squamous [47. CD95) Apoptosis competent: Increased lymphocyte Enhanced tumorigenesis: tumor necrosis Thymocytes after DNA damage numbers (splenomegaly.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. 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 . retina by Em–Myc (p53 up regulated and subventricular zone of the modulator of lateral ventricle).43] component 3 external granule layer. 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. B cell lymphomas driven [34. Vol. 22.24–29] X protein external granule layer. Killer. Brain tumors driven by [19–22. 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. 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.50] TRAIL-R2) cells of the brain.36. thymocytes and retinal cells after DNA damage Bbc3 (Puma) Apoptosis deficient: No spontaneous tumors Enhanced tumorigenesis: Bcl-2 binding Neurons (of the dentate gyrus. splenocytes. B cell lymphomas driven [33–38. Oncogene-expressing MEFs and B cell lymphomas driven [49. intestinal crypt by Em–Myc -acetate-induced cells.43] -myristate-13 keratinocytes.

suggesting a minimal role for Noxa in tumor Collectively. brain and encodes a tetraspan membrane protein that localizes to pancreatic b cell cancer. Gadd45a / be informed by identifying target genes selective to specific MEFs display chromosomal defects. 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. Vol. 22. p53-dependent apoptosis in a vari-ety of cell types [33. spontane-ous tumor development [33. 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. Because Noxa deficiency senescence target genes compromises apopto-sis less than Puma loss. Moreover. Mice deficient for the [33–35]. However. possibly those with non. Further-more. but far from mirror the phenotype of also insufficient to initiate tumor formation p53-null mice [57]. including Puma / mice develop tumors with similar kinetics to Em– tumor initiation. Loss of both Noxa and Puma is compared to controls [60]. 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. 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. mediated G1 arrest in response to DNA damage [57.Review Trends in Cell Biology February 2012. Perp suppressor activity because Bax deficiency acceler-ates overexpression is sufficient to induce apoptosis [46]. Analysis of Perp in mouse models has uncovered roles in participates in a transcription-independent pro-apoptotic function adhesion. In most but not all cancer models driven by because no spontaneous tumors are observed in double chemical carcinogens. and tumors were more proteins Noxa and Puma. Myc/Puma / mice. the p53 target spontaneous tumor 101 . such as acute DNA damage. p21 / MEFs are not immortal. Noxa and Puma gene amplification. It is noteworthy that Bax also [47]. similar to p53 / MEFs [65]. explain full p53 function. suggesting that other target genes.58]. indicat-ing that Perp loss promotes mediators of the apoptotic arm of the p53 pathway. deficiency nearly or completely abolishes DNA-damage-induced.45].44. With senescence similarly to wild-type MEFs [59]. whereas Bax. apoptosis and tumor suppression in vivo. Analysis of mice deficient for both Puma and Noxa has reinforced the dominant role for p53 / MEFs. undergoing Puma in p53-mediated apoptosis. p21 is important for the tumorigenesis G1 checkpoint response because p21 loss compromises p53- [34] and that Noxa deficiency fails to accelerate lympho. studies of p53 apoptosis target genes in Bax loss. Puma. as well as in B-cell lymphoma driven by desmosomes. Em–Myc/Noxa / nullizygosity promotes some aspect of tumorigenesis. that may not be phenotypes in chemical and genetic mouse cancer models (Table relevant for p53 action in tumor suppression.25]. Unlike magenesis in the Em–Myc model [36]. Bax does display tumor. and cell-cycle arrest. however. other stratified epithelia.34]. No. it is surprising that Puma / mice are not prone to p53 target genes Dr5 (also known as Killer and Trail receptor 2). respectively [31. 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]. were exposed to chronic UVB radiation [48].32]. in keratinocytes Em–Myc [26–29] (Table 1). levels of apoptosis in most cell types from reports suggested that p21-null mice do not display an enhanced tumor predisposition [57.58]. Although initial a few exceptions. and therefore do not specify the apoptotic Although Gadd45a deficiency alone does not predispose mice to cell fate [40. including aneuploidy and cellular responses. pro-gression or metastasis (Table 2) [61–64]. Perp tumorigenesis in mouse models of mammary. 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. activity (Table 2). 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. suppression [36]. as with 1) [49–54]. Perp-deficient mice The p53 target genes Pmaip1 and Bbc3 encode the BH3-only developed tumors with reduced latency. Collec-tively. intercellular adhesion junctions.34]. tumor studies have relied on conditional the requirement for Bax in p53-dependent apoptosis and tumor knock-out strategies [47]. irradiation or oncogene expression. p21 homozygous mutant mice [43]. suggesting that are induced by p53 to similar levels in the contexts of apoptosis Gadd45a is crucial for maintenance of genomic stability by p53.40–42]. 2 to tumor development in mouse models [24. that are essential advanced than in controls. these studies suggest that p21 deficiency can enable tumorigen-esis in select settings. and this may be explained by its specific affinity for Mcl1. Because Perp of p53. Other p53 target genes involved in senescence and cell-cycle apoptotic function(s). Puma both tumor initiation and progression [48]. 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]. which contrasts with the ability of Puma to bind all pro-survival Bcl-2 family members equivalently [39]. Thus. apoptosis compared to cell-cycle arrest. 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. 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. In the context of gene Perp is upregulated to higher levels during p53-mediated oncogene activation.56]. contribute to p53-mediated tumor arrest also demonstrate context-specific tumor-sup-pressor suppression in this model. however. tumorigene-sis in Em–Myc/Puma / mice is substantially delayed rel-ative to Em–Myc/p53+/ mice [36]. Importantly. suggesting that it is a central p53 apoptosis mediator (Table 1). although their roles are not sufficient to [36–38]. Interestingly.

growth context of oncogene activation. many of these the apoptotic pathway in tumor suppression. 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. V development. Although Ptprv / MEFs are deficient in result. 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). potentially involved in different p53 nally. 22. In fact. Pml important for p53 tumor-suppressor activity. DNA repair and other cellular processes. Vol. loss of Gadd45a both accelerates arrest. 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 [65.95] Growth arrest and Cell-cycle arrest of MEFs Thymic lymphomas after g-IR DNA damage. that multiple gene products. mice exhibit increased carcinogenesis follow-ing hyperproliferative signals or DNA damage. as described next. were employed [75]. the p53-inducible Ptprv gene encodes a transmem-brane effector functions.68]. Mice genes for tumor suppression in vivo in specific settings. as a tyrosine phosphatase [74]. This [69] essential for senescence triggered by oncogenic Ras point can only be unequivocally addressed by generating knock- expression [70. re-vealing that Gadd45a function is the tumor phenotypes of mice deficient for these genes are highly context-dependent [67. mice homozygous for this mutant allele and also null for p21 were deficient for any single target gene fail to recapitulate the generated. Nonetheless. In fact. 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. Collaborating p53 functions in tumor suppression To address the importance of the concerted action of dif- ferent p53 cellular functions in tumor suppression. Pml is a direct p53 target gene unrelated to their roles as direct effectors of p53 function. Exactly how Ptprv functions in tumor suppression remains un-clear.73]. 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. it is possible that and inhibits tumor onset. It is also possible loss can promote tumorigenesis in specific models [72.66]. Fi. In the target genes have p53-independent functions in apoptosis. 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. the striking tumor predisposition of p53-null mice might cell-cycle arrest responses to acute DNA damage. but are highly susceptible to deter-mine clearly whether p53 activation of a given gene is infection. thyroid tumors. collaborate in tumor suppression and that. No. 2 Table 2. Ptprv / mice do be explained by combined loss of several key p53 effector not develop spontaneous tumors within the first year of life. Pml-deficient mice do not exhibit a in mice with mutations in the p53 REs of specific target genes to spontaneous tumor predisposition. but functions. / mice develop tumors with shorter latency than either although loss of these targets can contribute to tumor p53R172P/R172P or p21 / mice [76].71]. DNA damage receptor type. confounding tumor analyses [72]. 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).Review Trends in Cell Biology February 2012. do develop more papillomas than wild-type mice after DMBA treatment [74]. p53 R172P/ R172P/p21 knockout mice do not display any spontaneous tumor phenotype. mice Perspectives on individual target-gene knockouts Although expressing the p53R172P mutant.62–64.

Strasser. p5325. p53 has two discrete transcriptional activation of many well-character-ized p53 target TADs. which lack tumor-suppressor activity. etc.26 is in a very context-dependent manner.53. A group of 14 candidate genes with probable roles in p53-mediated tumor suppression was defined by this analysis.26 Analysis of p53 TAD mutant knock-in mice and wild-type p53 represent novel p53 targets. 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. is unable to activate efficiently the expression of canonical p53 target genes. but is capable of genes. 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.77]. these findings are not incompatible with the notion model of oncogene-induced senescence. Surprisingly. still-unknown genes crucial for responses to acute DNA damage and oncogene activation.26. Vol. Noxa. The tumor-suppressor capability of p5325. Functional analysis of p53 transactivation domain (TAD) mutants identifies p53 target genes involved in tumor suppression. including p21.26 mutant. Review Trends in Cell Biology February 2012. we identified genes induced at least twofold and within 1. Phlda3. these compound Knock-in mice expressing p53 mutants carrying specific mutant mice are not abnormally cancer-prone. which all have tumor-suppressor activity. and that. but is a potent tumor suppressor. p5325. with L25Q. The capacity of p53 25.26. The majority of genes efficiently induced by both p5325. including Bax. p5325.54 and p53-null samples. 2 in p53R172P/R172P/p21 / and p53 / mice. (b) Comparison of gene expression profiles of p53 wild-type and p53-null HrasV12-MEFs reveals more than 1000 differentially expressed genes. As mentioned above. instead. with a few p53 target-gene knockout mice have failed to resolve fully the exceptions. Abhd4. This limited transactivation capability role of p53 transcriptional activation in tumor suppres-sion. 103 . which activates only a small subset of p53 target genes.54 TAD1 TAD2 TAD1 TAD2 p5353. induction of a small subset of p53-depen- dent genes is similar to that seen in wild-type cells [14. Perp and Puma. Furthermore.26. For example. Remarkably. generation of Puma / p21 / mice.15]. The ‘?’ denotes additional. Mutation of the first that p53-triggered cell-cycle arrest and apoptosis are crucial for TAD (termed p5325. although DNA damage. although strains has helped to address the contribution of transcrip-tional p53R172P/R172P/p21 / mice display longer overall survival.54.26 mutant to mediate only Although analysis of these mice has revealed tumor phenotypes particular p53 effector functions [14. p5325. Puma and Noxa. these data indicate that robust cannot be excluded. 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]. This list of 130 genes was then filtered for those commonly downregulated in human and mouse tumors according to the EBI Gene Atlas database. 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.26 is also unable to induce apoptosis or cell-cycle arrest in response to acute DNA damage. knock-in mouse potent transactivation of novel p53 (a) Acute DNA damage Oncogene activation (b) Tumor suppression Lack of tumor suppression wt p53 p5325. allows the 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. tumor suppression in diverse cell lineages in mouse models independent functions of p53 are required for tumor suppression (Figure 3a) [15.26. p53 mutant transcriptional activity in a Importantly. p5325.).5 standard deviations by p53wt. Using transcriptomics analysis of HrasV12-MEFs.W26S mutations) tumor suppression. A p53 TAD1 mutant. (Right) Transactivation by either TAD1 or TAD2 allows p53 responses to oncogene activation.26 can efficiently activate expression of only a limited number of mostly novel target genes. 22.26 can be explained by its ability to activate robustly a limited set of novel direct p53 target genes (Sidt2. including p21. either in cell-cycle arrest or apoptosis.26 to promote very low-level activation of various classical p53 target genes may also contribute to tumor suppression.54 p53 p53 p5325. (a) (Left) Transactivation domain 1 (TAD1) and robust transactivation of classical p53 target genes are required for responses to acute DNA damage. and recently a new approach utilizing p53 TAD mutant genes is dispensable for tumor suppression. of p53 function. but can promote tumor suppression in a number of mouse models. A similar rationale led to the suppression. including apoptosis and cell-cycle arrest. No. To enrich for genes with specific roles in tumor suppression.26 and p5353. the pos-sibility that transactivation.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. personal communication). we used gene expression profiling data generated with the p5325.53. relative to p5325.

L. therapeutic applications. 22. fundamental for p53 cel-lular responses and tumor suppression. transcription factor IIH (TFIIH) [80]. these studies lay the genes will more clearly unravel their precise roles in tumor groundwork for fully elaborating the intricate circuitry suppression.82] (Figure 2). to arrive at a group of 14 candidate tumor ly impaired for activation of the majority of p53 target genes.Review Trends in Cell Biology February 2012. TAD 1 interacts with TATA Although substitutions of F53Q. transcription by recruiting cofactors involved in transcriptional initiation and chromatin modification to the transcriptional start References sites of target genes. mutation of both TADs to interaction with the histone acetyl-transferases (HATs) p300 (p5325. p53 suppresses tumorigenesis by elaborating a new network of are directly bound by wild-type p53 by ChIP. some with demonstrated tumor- lost in human lung cancers [78]. p5353. and DNA repair competent to suppress the development of a wide range of tumor (Polk. These genes represent bona fide suppressor activity. 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.26. p53wt) were compared with those of cells double p53 target-gene knockout mutant mice. or both. but also have important in differ-ent cellular processes. types. J.54. suggesting that development in diverse contexts. Biochemical analysis of human p53 suggests 1 Brady. Ercc5). 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]. demonstrating that the ability of p53 including tumor suppression. this mutant is completely cytoskeletal function (Crip2. gene have remained surprisingly elusive. leading to the notion that the combined actions of proteins p53-null) [15]. including cell-cycle regulation. The tapestry of p53 tumor suppression will be further Acknowledgments illuminated by deciphering the molecular basis for differ-ent We thank Colleen Brady. Arap2).F54S within the second TAD binding protein (TBP) [79]. 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. 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. p53 acti-vates not be cited because of space constraints. are important for tumor suppression. 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 p53.53.26. recruitment of others. Defining the cofactor binding that of p53-null cells. For further refine-ment. 123. To identify such tumor-suppression target genes. analysis of the in identifying genes with relevance to human cancer. 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.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. Concluding remarks Deciphering the molecular mechanisms underlying p53 function Because the p5325.D. and Attardi. Notably. our studies are not incompatible with an additional role for p53 at the mitochondrion in tumor suppression. 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).26 mutant is deficient for efficient in tumor suppression is crucial for broadly under-standing cancer transactivation of most but not all p53 targets. (2010) p53 at a glance.53. suppression in vivo [15. p53 targets in one mouse. tumor-suppres-sion-associated target genes and which cellular Importantly. but collaborate in the genes. the molecular details of p53 action in tumor suppression activity.26. Thus.54) results in a transcriptional profile resem-bling and CBP [81. Future investigation of these new p53 target tumor-suppressor func-tion. by suggesting strategies to mitigate the migration and DNA repair. Although p53 is unequivocal-ly involved in tumor suppressor. 2 target genes. suppressors. which is severe- mouse cancers. Vol. 2527– that TAD1 and TAD2 2532 104 .77]. For example.54. but is a functional development. C. and are regulated in potential p53 tumor-suppres-sor mediators. and both TADs contribute tion capability or biological activity. Collectively. 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. Daniela Kenzelmann Brozˇ.53. Phlda3. We apologize to authors whose work could TAD requirements at different target genes. 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). Stud- tumor suppression (Figure 3b). Kank3. Intriguingly. 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.26. Given the function of these genes dispensable for tumor suppression. Moreover. Cell Sci. to activate transcription is indeed required for tumor suppression. minimal transactivation of canonical p53 target differentially interact with some cofactors. The p5325. these stud-ies have shed light on how p53 target genes because nearly all contain p53 consensus sites. One of these. an observation with p53 mutants defective for tumor suppression (p53 25. Beyond unraveling the the signatures derived from analysis of mouse cells were effective mechanisms of p53-mediated tumor suppression. 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. No. Rgs12). TAD2 specifically binds to (p5353.26. was previously de.A.54) alone do not compromise p53 transactiva. Mgmt. Jeanine Frey and Dadi Jiang for critical reading of the manuscript. These analyses and oncogenic signaling.

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