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p73ß-Mediated Apoptosis Requires p57^kip2 Induction and IEX-1 Inhibition

¹ Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York and ² Molecular Oncology Program, Spanish National Cancer Centre, Madrid, Spain

Requests for reprints: Carlos Cordon-Cardo, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY. Phone: 212-639-7746; Fax: 212-794-3186; E-mail: sgonzalez{at}cnio.es.

Similarly to p53, p73 and p73ß induce growth arrest and/or apoptosis in response to DNA damage or when exogenously expressed. However, how they trigger apoptosis remains unresolved. After stable transduction of either p73 or p73ß, a greater apoptotic response was observed for p73ß in both primary and tumor cells. Consistently, blocking ectopic and endogenous p73ß expression by specific shRNA significantly decreased apoptotic levels after DNA damage. We found that p73ß targets the apoptotic program at multiple levels: (i) facilitating caspase activation through p53-dependent signals and (ii) inducing p57^KIP2, while down-regulating c-IPA1 and IEX1 through a p53-independent mechanism. p73ß-mediated apoptosis was considerably reduced after inhibition of p57^KIP2 by small interfering RNA, IEX-1 overexpression, and in mouse embryo fibroblasts derived from p57^–/– mice. Data from this study offer evidence for the apoptotic activity exclusive of p73ß. In the clinical context, these results might have potential therapeutic implications, because p73ß could induce alternative apoptotic responses in tumors harboring p53 mutations.

Key Words: p73 • p73ß • apoptosis • tumorigenesis • cell cycle

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