title: Meiotic failure in cyclin A1-deficient mouse spermatocytes triggers apoptosis through intrinsic and extrinsic signaling pathways and 14-3-3 proteins.
abstract: Cyclin A1 (Ccna1), a member of the mammalian A type cyclins, is most abundantly expressed in spermatocytes and is essential for spermatogenesis in the mouse. Ccna1- deficient spermatocytes arrest at late meiotic prophase and undergo apoptosis. To further delineate the mechanisms and key factors involved in this process, we have examined changes in expression of genes involved in both intrinsic and extrinsic signaling pathways that trigger apoptosis in the mutant spermatocytes. Our results show that both pathways are involved, and that the factors involved in the intrinsic pathway were expressed earlier than those involved in the extrinsic pathway. We have also begun to identify in vivo Ccna1-interacting proteins, using an unbiased biochemical approach, and identified 14-3-3, a key regulator of apoptosis, as a Ccna1-interacting protein. Expression levels of 14-3-3 proteins remain unchanged between wild type and mutant testes but there were differences in the subcellular distribution. In wild type control, 14-3-3 is detected in both cytosolic and nuclear fractions whereas it is restricted to the cytoplasm in mutant testes. This differential distribution of 14-3-3 may contribute to the induction of apoptosis in Ccna1-deficient spermatocytes. These results provide insight into the apoptotic mechanisms and pathways that are triggered when progression through the meiotic cell cycle is defective in male gametogenesis.
authors.affiliation: Departments of Genetics & Development, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Panigrahi
authors.affiliation: Departments of Genetics & Development, Columbia University Medical Center, New York, New York, United States of America.|Program of Human Genetics, ICBM, Faculty of Medicine, University of Chile, Santiago, Chile.
authors.forename: Marcia
authors.initials: M
authors.lastname: Manterola
authors.affiliation: Departments of Genetics & Development, Columbia University Medical Center, New York, New York, United States of America.|Obstetrics & Gynecology, Columbia University Medical Center, New York, New York, United States of America.|Institute of Human Nutrition, Columbia University Medical Center, New York, New York, United States of America.|Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Wolgemuth
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D056750:Cyclin A1 / Q000235:genetics*; D005260:Female; D008297:Male; D008540:Meiosis; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013090:Spermatocytes / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D056750:Cyclin A1; D051057:Proto-Oncogene Proteins c-akt