The Role of P63 and P73 in Tumor Formation and Progression: Coming of Age Toward Clinical Usefulness Commentary Re: F

Vol. 9, 5437–5441, November 15, 2003 Clinical Cancer Research 5437

The Biology Behind The Role of p63 and p73 in Tumor Formation and Progression: Coming of Age Toward Clinical Usefulness Commentary re: F. Koga et al., Impaired p63 Expression Associates with Poor Prognosis and Uroplakin III Expression in Invasive Urothelial Carcinoma of the Bladder. Clin. Cancer Res., 9: 5501–5507, 2003, and P. Puig et al., p73 Expression in Human Normal and Tumor Tissues: Loss of p73␣ Expression Is Associated with Tumor Progression in Bladder Cancer. Clin. Cancer Res., 9: 5642–5651, 2003.

UteM.Moll domain (TAp63, TAp73), and inhibitory proteins lacking TA, ⌬ ⌬ Department of Pathology, State University of New York at Stony called Np63 and TAp73 (the collective name for four differ- Brook, Stony Brook, New York ent p73 TA-deficient forms). ⌬Np63 and ⌬TAp73 (mainly ⌬Np73) retain their DNA binding and tetramerization compe- INTRODUCTION tence and thus can act as powerful dominant-negative inhibitors p53 controls a powerful stress response by converting of p53 and of themselves (9–11). Moreover, both genes can upstream signals such as DNA damage, hypoxia, and oncogene undergo extensive COOH-terminal splicing producing three and deregulation into drastic biological endpoints. Depending on nine different species of TP63 and TP73, respectively, named ␣, cell type and damage, these are apoptosis, transient cell cycle ␤, ␥, etc. (␣ being full length). Different ‘tails’ further modulate arrest, or senescence, thereby stopping incipient cancer cells in the p53-like function of TA proteins. Structurally, the ␥ forms of their tracks and preventing tumor formation. One mechanism TP73 and TP63 most closely resemble p53. Surprisingly though, through which p53 works is its action as a transcription factor of whereas TAp63␥ is as powerful as p53 in transactivation and downstream targets that contribute to its biologic effect. A apoptosis assays (9), TAp73␥ is rather weak. The ␣ forms of second mechanism, specific for apoptosis, is a direct action of both genes contain an additional SAM motif, a conserved pro- p53 at the mitochondrial surface by promoting cytochrome c tein interaction module found in many proteins implicated in release (1). Hence, loss of p53 function is the preeminent development. Thus, TP73 and TP63 can generate an impressive finding in most cancers, whether directly through p53 mutation, modular complexity by combining a specific head with a par- loss of its upstream activator p14ARF (2), impaired nuclear ticular tail. In practice, this means that our understanding of retention (3, 4), up-regulation of its antagonist HDM2 (5), or their biological roles will greatly depend on knowing exactly mutations of downstream effectors such as Apaf-1 (6). which forms get expressed under what circumstances. Two novel p53 family members named p63 and p73 have remarkable structural similarity with p53 and thus generated Signaling to p73 and p63 by Oncogenes and instant expectations about analogous biological functions as DNA Damage tumor suppressor genes (7, 8). Six years later, we have un- earthed striking similarities but also surprising diversities, pos- The cellular and viral oncogenes E2F1, cMyc, and E1A can sibly because both genes give rise to proteins that have (a) induce and activate endogenous TAp73 for transactivation, apo- p53-agonistic functions, (b) p53-antagonistic functions, and (c) ptosis, and growth suppression in p53-deficient human tumor entirely novel functions. One reason for the remarkable diversity cells (12–14). E2F1 is a direct transcriptional activator of TP73 in p63/p73 function lies in their gene architecture (Fig. 1). TP53 but not of TP63. Because oncogene deregulation of E2F1 and 1 c-Myc is one of the most common genetic alterations in human produces a single protein with a TA, DNA-binding and oli- tumors, these findings might provide a physiologic mechanism gomerization domain as the three major modules. In contrast, for TAp73 overexpression in tumors. Endogenous p73 is acti- TP63 and TP73 products are complex and produce two diamet- vated for apoptosis in response to a wide variety of chemother- rically opposed protein classes via alternative promoters and apeutic drugs and ␥-irradiation in a pathway that channels exon splicing: p53-like proteins containing the transactivation through c-abl (15–17). Hence, p73-deficient cells have defective DNA damage checkpoints. Also, DNA damage-dependent activation of p73 might be partly responsible for p53-independent apoptosis (Fig. 2). Received 10/6/03; accepted 10/16/03. In normal peripheral T cells, the E2F1-p73 pathway medi- The costs of publication of this article were defrayed in part by the ates cell death after T-cell receptor activation (18). Consistent payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to with this notion, E2F1-null mice exhibit disruption of lymphatic indicate this fact. homeostasis with increased numbers of T cells and splenomeg- Requests for reprints: Dr. Ute M. Moll, Department of Pathology, aly (19, 20), suggesting that p73 plays a role in tumor surveil- SUNY at Stony Brook, BSTL9, R132-136, Stony Brook, New York lance pathways of lymphoid cells. Moreover, TP73 is transcrip- 11794-8691. Phone: (631) 444-2459; Fax: (631) 444-3424; E-mail: [email protected]. tionally silenced in acute lymphoblastic leukemia and Burkitt’s 1 The abbreviations used are: TA, transactivation; TCC, transitional cell lymphoma due to hypermethylation (21). Interestingly, in radi- carcinoma; RT-PCR, reverse transcription-PCR. ation-induced mouse T-cell lymphomas, the p73 locus under- Downloaded from clincancerres.aacrjournals.org on October 4, 2021. © 2003 American Association for Cancer Research. 5438 Role of p63 and p73 in Tumor Formation and Progression

files. Of note, the transcriptional effect of ⌬Np63␣ is most likely indirect (24). This agrees with the idea that TAp63 plays a more p53-like role, whereas ⌬Np63 has an antagonistic or even oncogenic role in cancer progression. A surprising cooperativity among p53/63/73 family members in inducing apoptosis was recently found in two experi- mental systems. In E1A-expressing mouse embryo fibroblasts and primary neuronal cultures, p63 and p73 expression is required to induce p53-dependent apoptosis in response to doxo- rubicin (25). As perhaps the first support in primary human cancers, the current study by Puig et al. (26) finds evidence for cooperativity of these three genes. TCC tumors with wild-type p53 and retained expression of p63/p73␣ are mostly superficial noninvasive lesions (84%), whereas tumors with mutant p53 and loss of p63/p73␣ are almost exclusively invasive lesions (93%). Fig. 1 Gene architecture of the p53 family. In contrast to the simple In contrast, no difference in tumor stage exists between the structure of the p53 protein that harbors the TA domain, the DNA- binding domain (DBD) and the oligomerization domain (OD)asthe wild-type p53/loss of p63/p73 group and the mutant p53/loss of three major modules, the products of TP73 and TP63 are complex and p63/73 group. also harbor a COOH-terminal SAM domain in the ␣ version. Both genes contain two promoters. The P1 promoter produces full-length proteins containing the TA domain, whereas the P2 promoter produces TA- TP63 and TP73: Roles in Development and deficient proteins with dominant-negative functions toward themselves Differentiation and toward p53. In the case of TP73, additional NH2-terminal splice Both genes play important and, despite their structural ⌬ variants of the P1 transcript produce N-like proteins (not all depicted). similarity, surprisingly unique roles in development and differ- In addition, extensive COOH-terminal splicing further modulates the p53-like functions of the TA proteins. entiation (Fig. 2). This is powerfully revealed by the developmental but noncancerous phenotypes of p63- and p73-deficient mice (9, 27, 28) and is in stark contrast to p53-null mice, which are highly tumor prone but lack an overt developmental pheno- goes loss of heterozygosity in 33% of the cases (22). Thus, in type. TP73 expression is required for selective neurogenesis, lymphoid tumors p73 shows some genetic features of a tumor pheromonal signaling, fluid dynamics of cerebrospinal fluid, suppressor gene. and immunity of the respiratory mucosa (28). p73-null mice Ectopic TAp63␥ in mouse erythroleukemia cells is stabi- have hippocampal dysgenesis, hydrocephalus due to hyperse- lized after treatment with UV, ␥-irradiation, or actinomycin D cretion of cerebrospinal fluid, purulent respiratory infections, but surprisingly induces erythroid differentiation rather than and show abnormal reproductive and social behavior due to apoptosis. Because ectopic TAp63␥ alone causes apoptosis in dysfunctional pheromone pathways regulated by the vomerona- baby hamster kidney cells (9), it hints at a functional versatility sal organ. Of note, the developing mouse brain and sympathetic ⌬ of TAp63␥ to induce differentiation under genotoxic circum- ganglia strongly express Np73 as the predominant p73 form ⌬ stances. (9, 10). Np73 plays an essential antiapoptotic role in central nervous system development, where it is required to counteract Transcriptional and Apoptotic Activity of p63 p53-mediated neuronal death during the normal “sculpting” of the developing brain (10). ⌬Np73 acts downstream of nerve and p73 growth factor in the nerve growth factor survival pathway (10). There are strong functional parallels among p53, TAp73, p73 also plays a role in cell differentiation. p73 expression ⌬ ⌬ and TAp63 on the one hand, and Np73 and Np63 on the increases during neuroblastoma differentiation in vitro. A sur- other hand. When overexpressed in cultured cells, TAp73 mim- ics the transcriptional activity and biological function of p53, independent of p53 status. p73/p53-responsive promoters in- clude genes involved in antiproliferative and proapoptotic stress responses (such as WAF1, 14-3-3␴, GADD45, PIGs, ribonucle- otide reductase p53R2, IGFBP3, and MDM2) and the repressed vascular endothelial growth factor promoter. However, based on their unique developmental function, p63/p73-specific targets almost certainly exist. Potency differences occur among COOH- terminal p73 isoforms. Similarly, TAp63␣ lacks significant transcriptional and apoptotic ability, whereas TAp63␥ is very potent in some cell systems (9), but not in others (23). Interest- ingly, gene profiling in osteosarcoma cells shows that ectopic ⌬Np63␣ and TAp63␣ each regulate a broad spectrum of genes with diverse roles in cell cycle, apoptosis, proliferation, and cell migration, but by and large represent opposing regulatory pro- Fig. 2 Roles of p63 and p73 in development and cancer.

vey of normal tissues in the current study by Puig et al. (26) with a classic suppressor function. In a wide spectrum of cancers suggests a role for p73␣ in the differentiation of stratified (breast, lung, esophagus, stomach, colon, ovary, liver, cholan- squamous epithelia (expressed in basal and parabasal cells) and giocarcinoma, squamous carcinoma, chronic myelogenous leuk transitional epithelia (expressed in all cell layers). blast crisis, acute myelogenous leukemia, ependymoma, and TP63 expression is essential for limb formation and epi- neuroblastoma), overexpression of TP73, rather than loss of dermal and adnexal morphogenesis, and p63-null mice are de- expression is seen, suggesting an oncogenic role in tumorigen- fective in all p63-expressing tissues. They show severe limb esis. The single exception to this picture are some lymphoid truncations and craniofacial malformations and fail to develop malignancies. Although p73 overexpression was found in B-cell skin, prostate, and mammary glands. The human counterparts chronic lymphocytic leukemia (33) and during differentiation of are heterozygous germ-line mutations of p63 causing the auto- myeloid leukemic cells (34), TP73 is transcriptionally silenced somal dominant disorders EEC (ectrodactyly, ectodermal dys- in some lymphoblastic leukemias and lymphomas due to pro- plasia, facial clefts) (29) and AEC (ankyloblepharon, ectoder- moter hypermethylation (21). mal dysplasia, clefting) (30). EEC mutations are missense Of note, many early studies measured global p73 levels. mutations within the DNA binding domain that prevent DNA Moreover, immunohistochemistry is unable to discriminate be- binding of TAp63 and destroy the dominant-negative properties tween TA and ⌬N forms of (p63 and) p73, due to lack of good of ⌬Np63 (29). AEC mutations are in the SAM domain. The discriminating antibodies. However, the recent discovery of mutant cannot interact with apobec 1-binding protein-1, thus dominant-negative ⌬TAp73 calls for isoform-specific assess- interfering with the essential splicing of fibroblast growth factor ment of p73 overexpression, and the field has started to use receptor-2 and inhibiting epithelial differentiation (30). isoform-specific RT-PCR. There is now emerging evidence that Like p73, p63 plays a role in the differentiation of stratified in some (nonurothelial) cancer types, the dominant-negative epithelia. Basal cells of normal human epithelium including the ⌬TAp73 forms, rather than TAp73, are the physiologically epidermis strongly express ⌬Np63 as the predominant isoform relevant components of tumor-associated p73 overexpression (9) but lose it gradually when they withdraw from the stem cell and are functionally overriding the often concomitant increase compartment (31). Thus, p63 has a fundamental role in the in TAp73. Frequent tumor-specific up-regulation of ⌬TAp73 is biology of keratinocyte stem cells (31). Controversy remains found in breast carcinoma, gynecological cancers, hepatocellu- whether the precise role of ⌬Np63 is in self renewal or in stem lar carcinoma, and neuroblastoma (11, 35, 36).2 Up-regulation cell differentiation (9, 27). What appears clear is that p63 is of ⌬Np73 was found to be an independent prognostic marker for probably not simply required for the proliferative capacity of reduced survival in neuroblastoma patients (36). Preferential stem cells because their immediate progeny, the TAC cells, are up-regulation of ⌬Np73 could also explain why global p73 equally proliferative but have already lost p63 expression (31). overexpression was found to be a poor prognostic factor in hepatocellular and colon carcinoma (37, 38). Experimentally, ⌬ Alteration of p63/p73 Expression in Human Cancer Np73 facilitates immortalization of primary fibroblasts and cooperates with oncogenic Ras in their transformation in vivo Current data on alterations of p63 and p73 expression in (39). human cancers are in some ways confusing, due to sometimes contradictory deductions made about their role as oncogene or tumor suppressor gene. However, because of the daunting func- Alteration of p63 Expression tional complexity of these gene products and the lack of easily Like TP73, TP63 lacks mutations in cancers. Instead, al- usable, specific antibodies, the field had been held back. Some terations in expression levels indicate a role for p63 in squamous early conclusions about oncogenic versus growth-suppressive and TCCs, albeit in a different way. In normal squamous epi- roles might have to be revised in the future. Illumination will thelia, ⌬Np63 is the predominant isoform. It is limited to pro- likely come when two points are now carefully taken into liferating basal and suprabasal cells (9), but is gradually lost when these cells withdraw from the stem cell compartment (31). consideration: (a) what is the predominant NH2-terminal isoform in the tissue of origin of a given cancer; and (b) which TP63 is located on chromosome 3q27–28 within a region fre- isoform is undergoing major alterations in the respective cancer quently amplified in squamous cell carcinomas (40), and the derivative. Together, this will go a long way toward crystalliz- maintenance of ⌬Np63 isoforms may contribute to keeping ing out the important changes from background noise in this squamous cells in a stem cell-like phenotype, thereby promoting complex system. The two current studies by Koga et al. (32) and tumor growth in this cancer type. Squamous cell carcinomas of Puig et al. (26) on large series of well-characterized TCCs the skin, lung, esophagus, and nasopharyngeal carcinoma (the represent an important advance in our biological understanding latter have almost always functional p53) express high levels of of their role in urothelial cancers and might even offer clinical ⌬Np63␣. Moreover, ⌬Np63 acts like an oncogene in Rat1a cells usefulness in predicting tumor behavior. in vivo (40). In prostate, p63 immunostaining is a reliable

Alteration of p73 Expression The roles of TP53 and TP73 in tumorigenesis seem to be 2 fundamentally different. In sharp contrast to TP53, the virtual N. Concin, K. Becker, N. Slade, S. Erster, E. Mueller-Holzner, H. Ulmer, G. Daxenbichler, A. Zeimet, R. Zeillinger, C. Marth, and U. M. absence of inactivating mutations, tumor-associated overexpres- Moll. Transdominant ⌬TAp73 isoforms are frequently up-regulated in sion of wild-type TP73 in many different human cancers, and ovarian cancer, and their deregulation is higher in p53 wild type than in lack of a cancer phenotype in TP73-null mice are inconsistent mutant tumors, submitted for publication.

marker for basal cells and identifies basal cell hyperplasia, Table 1 Shared and distinct properties of p53, p73, and p63 whereas prostatic adenocarcinoma, devoid of basal cells, is Shared properties: negative, providing a useful clinical marker for differential - Structural homologues diagnosis. Similarly, p63 is a marker of ductal myoepithelial - Activation by DNA-damaging agents cells in normal breast but is not expressed in invasive carci- - Proapoptotic functions; cooperate in the induction of apoptosis noma, which is devoid of this cell type. - Activation of many common target genes Distinct properties: - Distinct developmental functions p63 and p73 Expression in Urothelial Differentiation - Lack of p73/p63 mutations in human tumors - Lack of cancer-related phenotypes in p73/p63-null mice and Its Loss in Tumorigenesis - Different genomic organization of the p73/p63 gene gives rise to

In transitional epithelium, p63 and p73 appear to be im- several NH2-terminal isoforms with opposing properties portant differentiation factors that possibly remove cells from - Tumor-associated overexpression of wild-type p73/63 in many the actively cycling compartment. p63 is dispensable for forma- types of human cancers - Loss of p63/p73 expression during progression of urothelial tion of a nonspecific default epithelium but indispensable for cancers differentiation of a proper transitional urothelium (41). ⌬Np63, - Overexpression of ⌬Np63 in squamous cell carcinomas the predominant form, is strongly expressed in basal and inter- mediate cell layers of normal bladder urothelium, whereas it is undetectable in umbrella and stromal cells (9, 42, 43). Impor- tantly, several recent immunocytochemical studies found that biology are still a challenge. However, we are making progress. loss of p63 expression correlates with loss of urothelial differ- Clearly, they are not classic tumor suppressors. Rather, the entiation and is reproducibly associated with tumor progression existence of inhibitory versions of both genes and the intimate and invasiveness in bladder TCCs. Originally, a Korean RT- functional cross-talk among all family members endow them PCR study in 47 unspecified “bladder carcinomas” found up- with tissue-specific tumor suppressor, differentiation, or onco- regulation of ⌬Np63 with concomitant down-regulation of genic roles, which tumors then either down- or up-regulate to TAp63 in more than half the cases (44). However, in a more promote growth, prevent differentiation or evade apoptosis (Ta- detailed follow-up study from the United States of 160 well- ble 1). characterized TCCs, noninvasive papillary superficial tumors largely retained ⌬Np63 expression, whereas most invasive can- REFERENCES cers lost expression (41). 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Downloaded from clincancerres.aacrjournals.org on October 4, 2021. © 2003 American Association for Cancer Research. The Role of p63 and p73 in Tumor Formation and Progression: Coming of Age Toward Clinical Usefulness: Commentary re: F. Koga et al., Impaired p63 Expression Associates with Poor Prognosis and Uroplakin III Expression in Invasive Urothelial Carcinoma of the Bladder. Clin. Cancer Res., 9: 5501−5507, 2003, and P. Puig et al., p73 Expression in Human Normal and Tumor Tissues: Loss of p73 α Expression Is Associated with Tumor Progression in Bladder Cancer. Clin. Cancer Res., 9: 5642−5651, 2003.

Ute M. Moll

Clin Cancer Res 2003;9:5437-5441.

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