Role of p73 in malignancy: tumor suppressor or oncogene?

Abstract

The recently identified p53 family member, p73, shows substantial structural and functional homology with p53. However, despite the established role of p53 as a proto-type tumor suppressor, a similar function of p73 in malignancy is questionable. Overexpression of p73 can activate typical p53-responsive genes, and activation of p73 has been implicated in apoptotic cell death induced by aberrant cell proliferation and some forms of DNA-damage. These data together with the localization of TP73 on chromosome 1p36, a region frequently deleted in a variety of human tumors, led to the hypothesis that p73 has tumor suppressor activity just like p53. However, unlike p537/7 mice, p73 knockout mice do not develop tumors. Extensive studies on primary tumor tissues have revealed overexpression of wild-type p73 in the absence of p73 mutations instead, suggesting that p73 may augment, rather than inhibit tumor development. In contrast to p53, differential splicing of the TP73 gene locus gives rise to a complex pattern of interacting p73 isoforms with antagonistic functions. In fact, induction of apoptosis by increased levels of p73 can be blocked by both p53 mutants and the N-terminally truncated p73 isoforms, which were recently shown to possess oncogenic potential. In the light of these new findings the contradictory role of p73 in malignancy will be discussed.

Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

“…Thus, DNp73 overexpression would be one mechanism of inhibiting TAp73-and p53-dependent pro-apoptotic activity in response to chemotherapeutic drugs, leading to poor clinical outcome. 12,13 Consistently, exposure to genotoxic signals leads to the upregulation of TAp73 and the downregulation of DNp73, 14 hence allowing an effective apoptotic response to ensue. This indicates that the relative abundance of the two forms of p73 could be an important determinant of cellular fate during stress response, thereby regulating chemosensitivity.…”

Regulation of telomerase activity by the p53 family member p73

“…c-Myc) might therefore contribute to tumor formation in humans (Lin and Elledge, 2003). Since DNp73 is believed to function as an oncogene in the development of human cancer, we further investigated whether DNp73 expression is able to induce telomerase expression in telomerasenegative primary human fibroblasts (Stiewe and Pu¨tzer, 2002;Moll and Slade, 2004). As shown in Figure 8e, hTERT transcription is indeed induced in cells that stably express the DNp73a protein.…”

“…Indeed, in experimental systems, p73 showed many p53-like properties: it could bind to p53 DNA binding sites, transactivate p53-responsive genes and induce cell cycle arrest or apoptosis (Jost et al, 1997;Kaghad et al, 1997). However, despite an extensive search tumor-associated mutations of p73 were rarely identified (Stiewe and Pu¨tzer, 2002). Instead of mutational inactivation, overexpression of p73 has been reported for a wide variety of tumor entities and in some cases even correlated with an advanced tumor stage or poor prognostic parameters (Tannapfel et al, 1999;Stiewe and Pu¨tzer, 2002).…”

“…However, despite an extensive search tumor-associated mutations of p73 were rarely identified (Stiewe and Pu¨tzer, 2002). Instead of mutational inactivation, overexpression of p73 has been reported for a wide variety of tumor entities and in some cases even correlated with an advanced tumor stage or poor prognostic parameters (Tannapfel et al, 1999;Stiewe and Pu¨tzer, 2002). In contrast to mice lacking p53, p73-negative mice exhibit severe developmental defects, including hydrocephalus, hippocampal dysgenesis, chronic infections and inflammation, and abnormalities in the pheromone sensory pathway .…”

The p53 family inhibitor ΔNp73 interferes with multiple developmental programs

“…6,[8][9][10][11] These DN-isoforms are generated either by the use of alternative intronic promoters or by means of alternative splicing. [12][13][14] Since the DNisoforms retain their DNA-binding capacity, they bind to the promoters of target genes and act as transdominant-negative inhibitors of the full-length isoforms. 15 As shown in Figure 1a, N-terminally truncated p73a generated by both alternative splicing (DN AS ) or alternative promoter usage (DN AP ) functions as a potent inhibitor of all the major transactivating p53 family members (p53, TAp63 and TAp73).…”