p73beta-Mediated apoptosis requires p57kip2 induction and IEX-1 inhibition.
Similarly to p53, p73alpha and p73beta 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 p73alpha or p73beta, a greater apoptotic response was observed for p73beta in both primary and tumor cells. Consistently, blocking ectopic and endogenous p73beta expression by specific shRNA significantly decreased apoptotic levels after DNA damage. We found that p73beta targets the apoptotic program at multiple levels: (i) facilitating caspase activation through p53-dependent signals and (ii) inducing p57KIP2, while down-regulating c-IPA1 and IEX1 through a p53-independent mechanism. p73beta-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 p73beta. In the clinical context, these results might have potential therapeutic implications, because p73beta could induce alternative apoptotic responses in tumors harboring p53 mutations.
Gonzalez
Susana
S
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. sgonzales@cnio.es
Perez-Perez
Manuel M
MM
Hernando
Eva
E
Serrano
Manuel
M
Cordon-Cardo
Carlos
C
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D016147:Genes, Tumor Suppressor; D045325:HCT116 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D051017:Apoptosis Regulatory Proteins; C493964:CDKN1C protein, human; C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004268:DNA-Binding Proteins; C099815:IER3 protein, human; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins