Irinotecan-induced ovarian follicular apoptosis is attenuated by deleting the kinase domain of death-associated protein kinase.
Although death-associated protein kinase (DAPK) is a Ca2+/calmodulin-regulated serine/threonine kinase that plays important roles in various types of apoptotic cell death, there have been no reports of its tissue distributions and functions in female reproductive organs. By comparing C57BL/6 wild-type mice with DAPK-mutant mice lacking the 74-amino acid catalytic kinase domain of DAPK, the cellular distributions and biological functions of DAPK in murine ovaries were investigated. In situ hybridization analyses with sense and antisense riboprobes revealed that DAPK mRNA was selectively and highly expressed in granulosa cells in the ovaries of both types of mice. There were no significant differences in the body weights, ovarian weights and unstimulated ovarian follicular numbers between the wild-type and DAPK-mutant mice. Intraperitoneal injection of CPT-11, an anticancer topoisomerase I inhibitor that causes granulosa cell-specific apoptosis partly through Fas-Fas ligand (FasL) interactions in MCH mice, induced follicular apoptosis in both the wild-type and DAPK-mutant mice. However, the numbers of apoptotic follicles were significantly reduced in the DAPK-mutant mice. The Fas and FasL expression levels in the CPT-11-injected mice did not differ significantly between the wild-type and DAPK-mutant mice. These results indicate that DAPK positively regulates intracellular signaling pathways for CPT-11-induced granulosa cell apoptosis.
Li
Li
L
Department of Obstetrics and Gynecology, Wakayama Medical University, Wakayama 641-0012, Japan.
Tanaka
Tetsuji
T
Yukawa
Kazunori
K
Akira
Shizuo
S
Umesaki
Naohiko
N
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000737:chemistry* / Q000235:genetics*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D064550:Death-Associated Protein Kinases; D053222:Fas Ligand Protein; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006107:Granulosa Cells / Q000166:cytology; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D006080:Ovarian Follicle / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010053:Ovary / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D053222:Fas Ligand Protein; D000077146:Irinotecan; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002166:Camptothecin