p73 in Cancer

Abstract

p73 is a tumor suppressor belonging to the p53 family of transcription factors. Distinct isoforms are transcribed from the p73 locus. The use of 2 promoters at the N-terminus allows the expression of an isoform containing (TAp73) or not containing (ΔNp73) a complete N-terminal transactivation domain, with the latter isoform capable of a dominant negative effect over the former. In addition, both N-terminal variants are alternatively spliced at the C-terminus. TAp73 is a bona fide tumor suppressor, being able to induce cell death and cell cycle arrest; conversely, ΔNp73 shows oncogenic properties, inhibiting TAp73 and p53 functions. Here, we discuss the latest findings linking p73 to cancer. The generation of isoform specific null mice has helped in dissecting the contribution of TA versus ΔNp73 isoforms to tumorigenesis. The activity of both isoforms is regulated transcriptionally and by posttranslational modification. p73 dysfunction, particularly of TAp73, has been associated with mitotic abnormalities, which may lead to polyploidy and aneuploidy and thus contribute to tumorigenesis. Although p73 is only rarely mutated in cancer, the tumor suppressor actions of TAp73 are inhibited by mutant p53, a finding that has important implications for cancer therapy. Finally, we discuss the expression and role of p73 isoforms in human cancer, with a particular emphasis on the neuroblastoma cancer model. Broadly, the data support the hypothesis that the ratio between TAp73 and ΔNp73 is crucial for tumor progression and therapeutic response.

Keywords: knockout mice; mitosis; mutant p53; neuroblastoma; p73; rhabdomyosarcoma.

Figure 1.

Scheme of the p73 gene structure. Matured spliced isoforms and protein domains positions are shown (a). The structures of the Trp73 locus are depicted, and the exons originating the domains (shown in Figure 3a) are represented (b). Note the binding of E2F on P1 promoter and activation of ΔNp73 by p53 or TAp73. TA = transactivation domain; DBD = DNA binding domain; OD = oligomerization domain.

Figure 2.

p73 mouse models. Three mouse models for p73 are available. The p73 knockout mouse was developed by targeting the DNA binding domain and thus lacks expression of all p73 isoforms and shows severe developmental defects. Recently, N-terminus selective knockouts have been developed as well: TAp73 and ΔNp73 knockout mice show less severe developmental phenotype, but, importantly, depletion of TAp73 predisposes the animal to spontaneous tumorigenesis.

Figure 3.

p73 role in mitosis. p73 interaction with BubR1 is shown as a prerequisite for functional SAC activity (A). In the absence of TAp73, a dysfunctional SAC fails to arrest cells in mitosis, leading to aneuploidy, cancer, and infertility (B). TAp73 is also necessary to trigger mitotic cell death upon prolonged mitotic arrest or in the presence of reduced Bub1 levels. This cell death depends on SAC activity, but whether direct interaction between TAp73 and SAC components plays a role is unclear (C). SAC = spindle assembly checkpoint; MCD = mitotic cell death.

Figure 4.

p73 role in neuroblastoma. TAp73 plays a tumor suppressive role by inducing target genes (some of which are reported) that trigger cell cycle arrest, apoptosis, and differentiation. These activities are promoted by chemotherapeutic drugs, such as cisplatin or nutlin 3 or retinoic acid, and counteracted by the dominant negative function of ΔNp73. Two other important players are the transcription factors N-myc and E2F1, which upregulate and repress TAp73, respectively.