Irinotecan-induced ovarian follicular apoptosis is attenuated by deleting the kinase domain of death-associated protein kinase
Irinotecan-induced ovarian follicular apoptosis is attenuated by deleting the kinase domain of death-associated protein kinase
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DOI：
10.3892/ijo_00000216
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发表时间：
2009-04-01
影响因子：
5.2
通讯作者：
Umesaki, Naohiko
中科院分区：
文献类型：
--
作者：
Li, Li;Tanaka, Tetsuji;Umesaki, Naohiko
死亡相关蛋白激酶（death-associated protein kinase，DAPK）是一种由Ca ~（2+）/钙调素调节的丝氨酸/苏氨酸激酶，在多种类型的细胞凋亡中发挥重要作用，但其在女性生殖器官中的组织分布和功能尚未见报道。通过比较C57 BL/6野生型小鼠和缺失DAPK 74-氨基酸催化激酶结构域的DAPK突变型小鼠，研究了DAPK在小鼠卵巢中的细胞分布和生物学功能。正义和反义核糖核酸探针原位杂交分析表明，DAPK mRNA的选择性和高度表达的颗粒细胞在两种类型的小鼠卵巢。野生型和DAPK突变型小鼠之间的体重、卵巢重量和未刺激的卵巢卵泡数没有显著差异。CPT-11是一种抗癌拓扑异构酶I抑制剂，在MCH小鼠中部分通过Fas-Fas配体（FasL）相互作用引起颗粒细胞特异性凋亡，其腹腔注射可诱导野生型和DAPK突变小鼠的卵泡凋亡。然而，在DAPK突变小鼠中凋亡卵泡的数量显著减少。CPT-11注射小鼠的Fas和FasL表达水平在野生型和DAPK突变小鼠之间没有显著差异。这些结果表明，DAPK正调控CPT-11诱导的颗粒细胞凋亡的细胞内信号通路。
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.