Negative autoregulation of p73 and p53 by ΔNp73 in regulating differentiation and survival of human neuroblastoma cells

p73, mapped to 1p36.2–3, is a p53-related tumor suppressor but is also induced by the oncogene products such as E2F1, raising a question whether p73 is a tumor suppressor gene or oncogene. p73 has several splicing variants including ΔNp73 which lacks the NH2-terminal transactivation domain. In developing neurons, ΔNp73 is expressed abundantly and seems to inhibit the pro-apoptotic function of p53. However, the role of TAp73 and ΔNp73 as well as their regulatory mechanism in cell growth and differentiation of neuroblastoma cells are poorly understood. We have found that TAp73 directly activates the transcription of endogenous ΔNp73 by binding to the TAp73-specific target element located at position-76 to 57 within the ΔNp73 promoter region. ΔNp73 was physically associated with TAp73α, TAp73β and p53, and inhibited their transactivation activities when used reporters of Mdm2, Bax or ΔNp73 itself in SAOS-2 cells. Overexpression of ΔNp73 in SH-SY5Y neuroblastoma cells promoted cell survival by competing with p53 and TAp73 itself. Thus, our results suggest that the negative feedback regulation of TAp73 by its target ΔNp73 is a novel autoregulatory system for modulating cell survival and death, that is also functioning in neuroblastoma cells.