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Regulation of Caenorhabditis elegans p53/CEP-1-dependent germ cell apoptosis by Ras/MAPK signaling.
PLoS Genet. 2011 Aug; 7(8):e1002238.PG

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 also via a GLD-1-independent mechanism. In addition, we show that MPK-1 is phosphorylated and activated upon ionising radiation (IR) in late pachytene germ cells and that MPK-1-dependent CEP-1 activation may be in part direct, as these two proteins interact in a yeast two-hybrid assay. In summary, we report our novel finding that MAP kinase signaling controls CEP-1-dependent apoptosis by several different pathways that converge on CEP-1. Since apoptosis is also restricted to pachytene stage cells in mammalian germlines, analogous mechanisms regulating p53 family members are likely to be conserved throughout evolution.

Authors+Show Affiliations

Wellcome Trust Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21901106

Citation

Rutkowski, Rachael, et al. "Regulation of Caenorhabditis Elegans p53/CEP-1-dependent Germ Cell Apoptosis By Ras/MAPK Signaling." PLoS Genetics, vol. 7, no. 8, 2011, pp. e1002238.
Rutkowski R, Dickinson R, Stewart G, et al. Regulation of Caenorhabditis elegans p53/CEP-1-dependent germ cell apoptosis by Ras/MAPK signaling. PLoS Genet. 2011;7(8):e1002238.
Rutkowski, R., Dickinson, R., Stewart, G., Craig, A., Schimpl, M., Keyse, S. M., & Gartner, A. (2011). Regulation of Caenorhabditis elegans p53/CEP-1-dependent germ cell apoptosis by Ras/MAPK signaling. PLoS Genetics, 7(8), e1002238. https://doi.org/10.1371/journal.pgen.1002238
Rutkowski R, et al. Regulation of Caenorhabditis Elegans p53/CEP-1-dependent Germ Cell Apoptosis By Ras/MAPK Signaling. PLoS Genet. 2011;7(8):e1002238. PubMed PMID: 21901106.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regulation of Caenorhabditis elegans p53/CEP-1-dependent germ cell apoptosis by Ras/MAPK signaling. AU - Rutkowski,Rachael, AU - Dickinson,Robin, AU - Stewart,Graeme, AU - Craig,Ashley, AU - Schimpl,Marianne, AU - Keyse,Stephen M, AU - Gartner,Anton, Y1 - 2011/08/25/ PY - 2011/02/21/received PY - 2011/06/28/accepted PY - 2011/9/9/entrez PY - 2011/9/9/pubmed PY - 2012/1/13/medline SP - e1002238 EP - e1002238 JF - PLoS genetics JO - PLoS Genet VL - 7 IS - 8 N2 - 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 also via a GLD-1-independent mechanism. In addition, we show that MPK-1 is phosphorylated and activated upon ionising radiation (IR) in late pachytene germ cells and that MPK-1-dependent CEP-1 activation may be in part direct, as these two proteins interact in a yeast two-hybrid assay. In summary, we report our novel finding that MAP kinase signaling controls CEP-1-dependent apoptosis by several different pathways that converge on CEP-1. Since apoptosis is also restricted to pachytene stage cells in mammalian germlines, analogous mechanisms regulating p53 family members are likely to be conserved throughout evolution. SN - 1553-7404 UR - https://www.unboundmedicine.com/medline/citation/21901106/Regulation_of_Caenorhabditis_elegans_p53/CEP_1_dependent_germ_cell_apoptosis_by_Ras/MAPK_signaling_ L2 - https://dx.plos.org/10.1371/journal.pgen.1002238 DB - PRIME DP - Unbound Medicine ER -