Transactivation-deficient ΔTA-p73 inhibits p53 by direct competition for DNA binding. Implications for tumorigenesis

Abstract

The p53 family member p73 displays significant structural and functional homology to p53. However, instead of mutational inactivation, overexpression of wild-type p73 has been reported in various tumor types compared with normal tissues, arguing against a classical tumor suppressor function. Recently, N-terminally truncated, transactivation-deficient p73 isoforms (ΔTA-p73) have been identified as a second class of p73 proteins. Because overexpression of p73 in tumors includes ΔTA-p73, we further characterized these novel p73 isoforms. We show that ΔTA-p73 retains DNA-binding competence but lacks transactivation functions, resulting in an inability to induce growth arrest and apoptosis. Importantly, ΔTA-p73 acts as a dominant-negative inhibitor of p53 and full-length p73 (TA-p73). We demonstrate that inhibition of p53 involves competition for DNA binding, whereas TA-p73 can be inhibited by direct protein-protein interaction. Further, we show that up-regulation of endogenous p73 just like ectopic overexpression of ΔTA-p73 confers resistance to p53-mediated apoptosis induced by the chemotherapeutic agent H-7. Because inhibition of p53 is a common theme in human cancer, our data strongly support a role of ΔTA-p73 expression for tumor formation.