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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.

Department of Pathology, State University of New York at Stony Brook, Stony Brook, New York

INTRODUCTION

p53 controls a powerful stress response by converting upstream signals such as DNA damage, hypoxia, and oncogene deregulation into drastic biological endpoints. Depending on cell type and damage, these are apoptosis, transient cell cycle arrest, or senescence, thereby stopping incipient cancer cells in their tracks and preventing tumor formation. One mechanism through which p53 works is its action as a transcription factor of downstream targets that contribute to its biologic effect. A second mechanism, specific for apoptosis, is a direct action of p53 at the mitochondrial surface by promoting cytochrome c release (1) . Hence, loss of p53 function is the preeminent finding in most cancers, whether directly through p53 mutation, loss of its upstream activator p14ARF (2) , impaired nuclear retention (3 , 4) , up-regulation of its antagonist HDM2 (5) , or mutations of downstream effectors such as Apaf-1 (6) .

Two novel p53 family members named p63 and p73 have remarkable structural similarity with p53 and thus generated instant expectations about analogous biological functions as tumor suppressor genes (7 , 8) . Six years later, we have unearthed striking similarities but also surprising diversities, possibly because both genes give rise to proteins that have (a) p53-agonistic functions, (b) p53-antagonistic functions, and (c) entirely novel functions. One reason for the remarkable diversity in p63/p73 function lies in their gene architecture (Fig. 1) . TP53 produces a single protein with a TA,¹ DNA-binding and oligomerization domain as the three major modules. In contrast, TP63 and TP73 products are complex and produce two diametrically opposed protein classes via alternative promoters and exon splicing: p53-like proteins containing the transactivation domain (TAp63, TAp73), and inhibitory proteins lacking TA, called Np63 and TAp73 (the collective name for four different p73 TA-deficient forms). Np63 and TAp73 (mainly Np73) retain their DNA binding and tetramerization competence and thus can act as powerful dominant-negative inhibitors of p53 and of themselves (9, 10, 11) . Moreover, both genes can undergo extensive COOH-terminal splicing producing three and nine different species of TP63 and TP73, respectively, named , ß, , etc. ( being full length). Different ‘tails’ further modulate the p53-like function of TA proteins. Structurally, the forms of TP73 and TP63 most closely resemble p53. Surprisingly though, whereas TAp63 is as powerful as p53 in transactivation and apoptosis assays (9) , TAp73 is rather weak. The forms of both genes contain an additional SAM motif, a conserved protein interaction module found in many proteins implicated in development. Thus, TP73 and TP63 can generate an impressive modular complexity by combining a specific head with a particular tail. In practice, this means that our understanding of their biological roles will greatly depend on knowing exactly which forms get expressed under what circumstances.

View larger version (36K): [in this window] [in a new window]   Fig. 1. Gene architecture of the p53 family. In contrast to the simple structure of the p53 protein that harbors the TA domain, the DNA-binding domain (DBD) and the oligomerization domain (OD) as the three major modules, the products of TP73 and TP63 are complex and 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-deficient proteins with dominant-negative functions toward themselves and toward p53. In the case of TP73, additional NH2-terminal splice variants of the P1 transcript produce N-like proteins (not all depicted). In addition, extensive COOH-terminal splicing further modulates the p53-like functions of the TA proteins.

The cellular and viral oncogenes E2F1, cMyc, and E1A can induce and activate endogenous TAp73 for transactivation, apoptosis, and growth suppression in p53-deficient human tumor cells (12, 13, 14) . E2F1 is a direct transcriptional activator of TP73 but not of TP63. Because oncogene deregulation of E2F1 and c-Myc is one of the most common genetic alterations in human tumors, these findings might provide a physiologic mechanism for TAp73 overexpression in tumors. Endogenous p73 is activated for apoptosis in response to a wide variety of chemotherapeutic drugs and -irradiation in a pathway that channels through c-abl (15, 16, 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) .

View larger version (16K): [in this window] [in a new window]   Fig. 2. Roles of p63 and p73 in development and cancer.

Ectopic TAp63 in mouse erythroleukemia cells is stabilized after treatment with UV, -irradiation, or actinomycin D but surprisingly induces erythroid differentiation rather than apoptosis. Because ectopic TAp63 alone causes apoptosis in baby hamster kidney cells (9) , it hints at a functional versatility of TAp63 to induce differentiation under genotoxic circumstances.

Transcriptional and Apoptotic Activity of p63 and p73

There are strong functional parallels among p53, TAp73, and TAp63 on the one hand, and Np73 and Np63 on the other hand. When overexpressed in cultured cells, TAp73 mimics the transcriptional activity and biological function of p53, independent of p53 status. p73/p53-responsive promoters include genes involved in antiproliferative and proapoptotic stress responses (such as WAF1, 14-3-3, GADD45, PIGs, ribonucleotide 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) . Interestingly, 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 profiles. 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 experimental 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 doxorubicin (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%). In contrast, no difference in tumor stage exists between the wild-type p53/loss of p63/p73 group and the mutant p53/loss of p63/73 group.

TP63 and TP73: Roles in Development and Differentiation

Both genes play important and, despite their structural similarity, surprisingly unique roles in development and differentiation (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 phenotype. TP73 expression is required for selective neurogenesis, pheromonal signaling, fluid dynamics of cerebrospinal fluid, and immunity of the respiratory mucosa (28) . p73-null mice have hippocampal dysgenesis, hydrocephalus due to hypersecretion of cerebrospinal fluid, purulent respiratory infections, and show abnormal reproductive and social behavior due to dysfunctional pheromone pathways regulated by the vomeronasal organ. Of note, the developing mouse brain and sympathetic ganglia strongly express Np73 as the predominant p73 form (9 , 10) . Np73 plays an essential antiapoptotic role in central nervous system development, where it is required to counteract p53-mediated neuronal death during the normal "sculpting" of the developing brain (10) . Np73 acts downstream of nerve growth factor in the nerve growth factor survival pathway (10) . p73 also plays a role in cell differentiation. p73 expression increases during neuroblastoma differentiation in vitro. A survey of normal tissues in the current study by Puig et al. (26) suggests a role for p73 in the differentiation of stratified squamous epithelia (expressed in basal and parabasal cells) and transitional epithelia (expressed in all cell layers).

TP63 expression is essential for limb formation and epidermal and adnexal morphogenesis, and p63-null mice are defective in all p63-expressing tissues. They show severe limb truncations and craniofacial malformations and fail to develop skin, prostate, and mammary glands. The human counterparts are heterozygous germ-line mutations of p63 causing the autosomal dominant disorders EEC (ectrodactyly, ectodermal dysplasia, facial clefts) (29) and AEC (ankyloblepharon, ectodermal dysplasia, clefting) (30) . EEC mutations are missense mutations within the DNA binding domain that prevent DNA binding of TAp63 and destroy the dominant-negative properties of Np63 (29) . AEC mutations are in the SAM domain. The mutant cannot interact with apobec 1-binding protein-1, thus interfering with the essential splicing of fibroblast growth factor receptor-2 and inhibiting epithelial differentiation (30) .

Like p73, p63 plays a role in the differentiation of stratified epithelia. Basal cells of normal human epithelium including the epidermis strongly express Np63 as the predominant isoform (9) but lose it gradually when they withdraw from the stem cell compartment (31) . Thus, p63 has a fundamental role in the biology of keratinocyte stem cells (31) . Controversy remains whether the precise role of Np63 is in self renewal or in stem cell differentiation (9 , 27) . What appears clear is that p63 is probably not simply required for the proliferative capacity of stem cells because their immediate progeny, the TAC cells, are equally proliferative but have already lost p63 expression (31) .

Alteration of p63/p73 Expression in Human Cancer

Current data on alterations of p63 and p73 expression in 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 functional complexity of these gene products and the lack of easily usable, specific antibodies, the field had been held back. Some early conclusions about oncogenic versus growth-suppressive roles might have to be revised in the future. Illumination will likely come when two points are now carefully taken into consideration: (a) what is the predominant NH₂-terminal isoform in the tissue of origin of a given cancer; and (b) which isoform is undergoing major alterations in the respective cancer derivative. Together, this will go a long way toward crystallizing out the important changes from background noise in this complex system. The two current studies by Koga et al. (32) and Puig et al. (26) on large series of well-characterized TCCs represent an important advance in our biological understanding of their role in urothelial cancers and might even offer clinical usefulness in predicting tumor behavior.

Alteration of p73 Expression

The roles of TP53 and TP73 in tumorigenesis seem to be fundamentally different. In sharp contrast to TP53, the virtual absence of inactivating mutations, tumor-associated overexpression of wild-type TP73 in many different human cancers, and lack of a cancer phenotype in TP73-null mice are inconsistent with a classic suppressor function. In a wide spectrum of cancers (breast, lung, esophagus, stomach, colon, ovary, liver, cholangiocarcinoma, squamous carcinoma, chronic myelogenous leuk blast crisis, acute myelogenous leukemia, ependymoma, and neuroblastoma), overexpression of TP73, rather than loss of expression is seen, suggesting an oncogenic role in tumorigenesis. The single exception to this picture are some lymphoid malignancies. Although p73 overexpression was found in B-cell chronic lymphocytic leukemia (33) and during differentiation of myeloid leukemic cells (34) , TP73 is transcriptionally silenced in some lymphoblastic leukemias and lymphomas due to promoter hypermethylation (21) .

Of note, many early studies measured global p73 levels. Moreover, immunohistochemistry is unable to discriminate between TA and N forms of (p63 and) p73, due to lack of good discriminating antibodies. However, the recent discovery of dominant-negative TAp73 calls for isoform-specific assessment of p73 overexpression, and the field has started to use isoform-specific RT-PCR. There is now emerging evidence that in some (nonurothelial) cancer types, the dominant-negative TAp73 forms, rather than TAp73, are the physiologically relevant components of tumor-associated p73 overexpression and are functionally overriding the often concomitant increase in TAp73. Frequent tumor-specific up-regulation of TAp73 is found in breast carcinoma, gynecological cancers, hepatocellular carcinoma, and neuroblastoma (11 , 35 , 36) .² Up-regulation of Np73 was found to be an independent prognostic marker for reduced survival in neuroblastoma patients (36) . Preferential up-regulation of Np73 could also explain why global p73 overexpression was found to be a poor prognostic factor in hepatocellular and colon carcinoma (37 , 38) . Experimentally, Np73 facilitates immortalization of primary fibroblasts and cooperates with oncogenic Ras in their transformation in vivo (39) .

Alteration of p63 Expression

Like TP73, TP63 lacks mutations in cancers. Instead, alterations in expression levels indicate a role for p63 in squamous and TCCs, albeit in a different way. In normal squamous epithelia, Np63 is the predominant isoform. It is limited to proliferating basal and suprabasal cells (9) , but is gradually lost when these cells withdraw from the stem cell compartment (31) . TP63 is located on chromosome 3q27–28 within a region frequently amplified in squamous cell carcinomas (40) , and the maintenance of Np63 isoforms may contribute to keeping squamous cells in a stem cell-like phenotype, thereby promoting tumor growth in this cancer type. Squamous cell carcinomas of the skin, lung, esophagus, and nasopharyngeal carcinoma (the latter have almost always functional p53) express high levels of Np63. Moreover, Np63 acts like an oncogene in Rat1a cells in vivo (40) . In prostate, p63 immunostaining is a reliable marker for basal cells and identifies basal cell hyperplasia, whereas prostatic adenocarcinoma, devoid of basal cells, is negative, providing a useful clinical marker for differential diagnosis. Similarly, p63 is a marker of ductal myoepithelial cells in normal breast but is not expressed in invasive carcinoma, which is devoid of this cell type.

p63 and p73 Expression in Urothelial Differentiation and Its Loss in Tumorigenesis

In transitional epithelium, p63 and p73 appear to be important differentiation factors that possibly remove cells from the actively cycling compartment. p63 is dispensable for formation of a nonspecific default epithelium but indispensable for differentiation of a proper transitional urothelium (41) . Np63, the predominant form, is strongly expressed in basal and intermediate cell layers of normal bladder urothelium, whereas it is undetectable in umbrella and stromal cells (9 , 42 , 43) . Importantly, several recent immunocytochemical studies found that loss of p63 expression correlates with loss of urothelial differentiation and is reproducibly associated with tumor progression and invasiveness in bladder TCCs. Originally, a Korean RT-PCR study in 47 unspecified "bladder carcinomas" found up-regulation of Np63 with concomitant down-regulation of TAp63 in more than half the cases (44) . However, in a more detailed follow-up study from the United States of 160 well-characterized TCCs, noninvasive papillary superficial tumors largely retained Np63 expression, whereas most invasive cancers lost expression (41) . Subsequently, a Japanese study on 72 TTC tumors confirmed the latter findings (43) . Interestingly, diminished Np63 expression correlated with reduced ß-catenin expression, suggesting defective cell-cell adherent junctions (43) . The current study by Koga et al. (32) again confirms the association between loss of Np63 and histological tumor progression but goes one step further toward clinicopathological implications, coming close to identifying Np63 loss as an independent prognostic marker for poor outcome (marginal significance P = 0.074). Less is known regarding alterations of p73 in bladder cancer, although the current paper by Puig et al. (26) suggests a similar alteration associated with tumor progression. Again, an early RT-PCR study measuring global p73 expression found overexpression in 95% of invasive TCCs (45) . However, the current immunohistochemical survey on 154 well-characterized primary bladder tumors by Puig et al. (26) , using an antibody that sees all -forms (TA and N), now finds that most invasive TCC tumors lose p73 expression, whereas over half of the superficial noninvasive cancers retain p73 expression. Together, these data are strong support for the biological relevance of p63 and p73 in the progression of urothelial carcinomas. Future studies are needed to substantiate their independent prognostic value for clinical outcome.

CONCLUSIONS

The discovery of two structural homologues of p53 generated instant excitement and quick expectations about their p53-like biological functions. We now know that in development p63 and p73 clearly have novel, p53-independent functions. There is also mounting evidence that both genes play an important role in human cancer, although their precise roles in tumor biology are still a challenge. However, we are making progress. Clearly, they are not classic tumor suppressors. Rather, the existence of inhibitory versions of both genes and the intimate functional cross-talk among all family members endow them with tissue-specific tumor suppressor, differentiation, or oncogenic roles, which tumors then either down- or up-regulate to promote growth, prevent differentiation or evade apoptosis (Table 1) .

FOOTNOTES

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints:Dr. Ute M. Moll, Department of Pathology, SUNY at Stony Brook, BSTL9, R132-136, Stony Brook, New York 11794-8691. Phone: (631) 444-2459; Fax: (631) 444-3424; E-mail: umoll{at}notes.cc.sunysb.edu

¹ The abbreviations used are: TA, transactivation; TCC, transitional cell carcinoma; RT-PCR, reverse transcription-PCR.

² N. Concin, K. Becker, N. Slade, S. Erster, E. Mueller-Holzner, H. Ulmer, G. Daxenbichler, A. Zeimet, R. Zeillinger, C. Marth, and U. M. Moll. Transdominant TAp73 isoforms are frequently up-regulated in ovarian cancer, and their deregulation is higher in p53 wild type than in mutant tumors, submitted for publication.

Received 10/ 6/03; accepted 10/16/03.

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