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.

GLS2 is transcriptionally regulated by p73 and contributes to neuronal differentiation

“…[11][12][13][14][15] It is involved in several biological processes, such as cell death, [16][17][18][19] differentiation, [20][21][22] neuronal stem cell maintenance, [23][24][25][26] the amino acid Glutamine is converted into Glutamate by a deamidation reaction catalyzed by the enzyme Glutaminase (GLS). two isoforms of this enzyme have been described, and the GLS2 isoform is regulated by the tumor suppressor gene p53.…”

Mechanism of TAp73 inhibition by ΔNp63 and structural basis of p63/p73 hetero-tetramerization

“…Although p53 is the main tumor suppressor, p73 has additional important developmental roles 1 besides its action as a tumor suppressor. 2 The connection of p63 and tumor development, however, is less obvious. So far two main functions have been identified for p63 that are connected to two different isoforms of the protein.…”

ΔNp63 regulates select routes of reprogramming via multiple mechanisms

“…Thus, full-length TAp63/TAp73, which carry the N-terminal transcriptional activation (TA) domain, can induce cell cycle arrest and apoptosis similar to p53, whereas the N-terminally truncated DNp63/DNp73 often act in a dominant-negative manner by inhibiting full-length family members, including p53. [35][36][37] p63 and p73 have been implicated in oncogenesis, [35][36][37] but their role in somatic reprogramming has barely been investigated. 34,38 Here we show for the first time that DNp63 is a potent positive regulator of reprogramming.…”