p53 induces the expression of its antagonist p73ΔN, establishing an autoregulatory feedback loop

Abstract

The p53 tumor suppressor protein activates transcription and induces cell death. A close homologue of p53, termed p73, is expressed in transactivating (TA) forms that induce growth arrest and apoptosis much like p53. However, the p73 gene contains a second promoter, giving rise to the expression of p73DN, a species of p73 proteins that lack the N-terminal transactivation domain. We show here that the expression of p73DN is induced by p53 on the mRNA and protein level. The promoter that regulates p73DN expression in human cells was cloned and found to be activated by p53, as well as by p73TA, directly through a specific DNA element. The p73DN proteins, that are thereby expressed, bound to p53-responsive promoter DNA, competed with p53 for DNA binding, antagonized the activation of transcription by p53, and prevented p53-induced cell death. In addition, a transcriptional repressor domain was identified within the splicing variant p73DNa. The combination of p73DNa and mdm2 antagonized p53 more strongly than either p73Na or mdm2 alone. Blocking endogenous p73DN by a trans dominant fragment, or its removal by siRNA, increased the activity of a p53-responsive promoter in cells that contain a wild type p53 gene. Thus, the induction of p73DN expression by p53 establishes an autoregulatory feedback loop that keeps the trigger of cell death under tight control.

Regulation of telomerase activity by the p53 family member p73

“…We and other groups have recently demonstrated that tumor cells frequently overexpress N-terminally truncated p73 isoforms that result from abberant splicing or the use of an alternative intronic promoter (Fillippovich et al, 2001;Grob et al, 2001;Kartasheva et al, 2002;Stiewe et al, 2002a, b;Zaika et al, 2002;Pu¨tzer et al, 2003). These DNp73 proteins act as dominant-negative inhibitors of the proapoptotic p53 family members by formation of transactivation-defective heteromeric complexes (Grob et al, 2001;Kartasheva et al, 2002;Stiewe et al, 2002a). Such a dominant-negative function of DNp73 has also been observed in this study with respect to hTERT regulation.…”

“…In contrast to downregulation of hTERT by differentiation or proapoptotic stress signals, hTERT is typically activated in immortal cells and established tumors . We and other groups have recently demonstrated that tumor cells frequently overexpress N-terminally truncated p73 isoforms that result from abberant splicing or the use of an alternative intronic promoter (Fillippovich et al, 2001;Grob et al, 2001;Kartasheva et al, 2002;Stiewe et al, 2002a, b;Zaika et al, 2002;Pu¨tzer et al, 2003). These DNp73 proteins act as dominant-negative inhibitors of the proapoptotic p53 family members by formation of transactivation-defective heteromeric complexes (Grob et al, 2001;Kartasheva et al, 2002;Stiewe et al, 2002a).…”

Expression levels of p53 and p73 isoforms in stage I and stage III ovarian cancer

“…Wtp53 tumours had higher TAp73 levels than mutant p53 tumours, a finding that is not easily explained (wtp53 has been shown to transactivate ΔNp73 from the P2 promoter but not the P1 promoter 22 ). On the other hand, despite the drop in ΔNp73 mRNA levels in stage III, immunoblot analysis revealed that the total levels of ΔNp73 protein were comparable between the two stages.…”

ΔNp73 stabilises TAp73 proteins but compromises their function due to inhibitory hetero-oligomer formation

“…Promoter competition by DNp73 at TAp73/p53 response elements is another transdominant mechanism. 11,12 Highly prevalent tumor-specific upregulation of DNp73 has already been found in several studies. 8,9,[16][17][18][19] For example, we reported that DNp73/DN 0 p73 transcripts are overexpressed in 73% of 37 gynecological cancers and DN 0 p73 transcripts are upregulated in 87% of 100 ovarian cancers.…”

“…[9][10][11][12] They act as powerful inhibitors of p53 and TAp73 since they retain their DNA-binding and tetramerization competence. [7][8][9]11,13,14 In cultured cells, DNp73 abrogates the suppressive activity of p53 and TAp73 and inactivates their ability to induce apoptosis and cell cycle arrest.…”