Autoinhibitory Regulation of p73 by ΔNp73 To Modulate Cell Survival and Death through a p73-Specific Target Element within the ΔNp73 Promoter

Abstract

P73 is a p53-related tumor suppressor but is also induced by oncogene products such as E2F-1, raising a question as to whether p73 is a tumor suppressor gene or oncogene. Unlike p53, p73 has several variants, including ΔNp73, which lacks the NH₂-terminal transactivation domain. Although, in developing neurons, ΔNp73 is expressed abundantly and seems to inhibit the proapoptotic function of p53, the role of p73 and ΔNp73 and their regulatory mechanism in cell growth and differentiation are poorly understood. Here we report that p73, but not p53, directly activates the transcription of endogenous ΔNp73 by binding to the p73-specific target element located at positions −76 to −57 within the ΔNp73 promoter region. The activation of ΔNp73 promoter by p63 was marginal. ΔNp73 was associated with p73α, p73β, and p53, as demonstrated by immunoprecipitation assays, and inhibited their transactivation activities when we used reporters of Mdm2, Bax, or ΔNp73 itself in SAOS-2 cells. Furthermore, induction or overexpression of ΔNp73 promoted cell survival by competing with p53 and p73 itself. Thus, our results suggest that the negative feedback regulation of p73 by its target ΔNp73 is a novel autoregulatory system for modulating cell survival and death.