regulation of caenorhabditis elegans p53cep-1–dependent germ cell apoptosis by rasmapk signaling监管rasmapk秀丽隐杆线虫p53cep-1-dependent生殖细胞凋亡的信号.pdfVIP

Regulation of Caenorhabditis elegans p53/CEP-1–Dependent Germ Cell Apoptosis by Ras/MAPK Signaling 1 2 2 1 1¤ Rachael Rutkowski , Robin Dickinson , Graeme Stewart , Ashley Craig , Marianne Schimpl , Stephen M. 2 1 Keyse , Anton Gartner * 1 Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, United Kingdom, 2 Cancer Research UK Stress Response Laboratory, Medical Research Institute, Ninewells Hospital and Medical School, Dundee, United Kingdom Abstract Maintaining genome stability in the germline is thought to be an evolutionarily ancient role of the p53 family. The sole Caenorhabditis elegans p53 family member CEP-1 is required for apoptosis induction in meiotic, late-stage pachytene germ cells in response to DNA damage and meiotic recombination failure. In an unbiased genetic screen for negative regulators of CEP-1, we found that increased activation of the C. elegans ERK orthologue MPK-1, resulting from either loss of the lip-1 phosphatase or activation of let-60 Ras, results in enhanced cep-1–dependent DNA damage induced apoptosis. We further show that MPK-1 is required for DNA damage–induced germ cell apoptosis. We provide evidence that MPK-1 signaling regulates the apoptotic competency of germ cells by restricting CEP-1 protein expression to cells in late pachytene. Restricting CEP-1 expression to cells in late pachytene is thought to ensure that apoptosis doesn’t occur in earlier-stage cells where meiotic recombination occurs. MPK-1 signaling regulates CEP-1 expression in part by regulating the levels of GLD-1, a translational repressor of CEP-1, but