Stem cell factor/c-kit up-regulates cyclin D3 and promotes cell cycle progression via the phosphoinositide 3-kinase/p70 S6 kinase pathway in spermatogonia
Stem cell factor/c-kit up-regulates cyclin D3 and promotes cell cycle progression via the phosphoinositide 3-kinase/p70 S6 kinase pathway in spermatogonia
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DOI：
10.1074/jbc.m002218200
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发表时间：
2000-08-18
影响因子：
4.8
通讯作者：
Dym, M
中科院分区：
文献类型：
--
作者：
Feng, LX;Ravindranath, N;Dym, M
干细胞因子(SCF)/c-KIT在造血、黑素生成和精子发生中起着重要的调节作用，在睾丸中，SCF/c-KIT系统被认为调节生殖细胞的增殖、减数分裂和凋亡，体内和体外对A型精原细胞的研究表明，SCF诱导DNA合成和增殖。然而，SCF/c-kit这一功能的信号通路尚未阐明。我们现在证明，SCF激活磷脂酰肌醇3-激酶(P13-K)和p70S6K(P70S6K)，而雷帕霉素是依赖雷帕霉素的p70S6K抑制剂的FRAP/哺乳动物靶点，完全抑制SCF诱导的精原细胞原代培养中溴脱氧尿苷的掺入，SCF通过对Wortmannin和雷帕霉素敏感的途径诱导细胞周期蛋白D3的表达和视网膜母细胞瘤蛋白的磷酸化。此外，SCF/c-kit/P13-K催化使用AKT而不是蛋白激酶C-Zeta激活p70S6K，显性的AKT-K179M：完全取消P13-K亚单位p110，10，K179M诱导的p70S6K磷酸化。因此，SCF/c-KIT通过雷帕霉素敏感的P13-K/AKT/p70S6K/Cyclin D3途径促进精原细胞的增殖。
Stem cell factor (SCF)/c-kit plays an important role in the regulation of hematopoiesis, melanogenesis, and spermatogenesis, In the testis, the SCF/c-kit system is believed to regulate germ cell proliferation, meiosis, and apoptosis, Studies with type A spermatogonia in vivo and in vitro have indicated that SCF induces DNA synthesis and proliferation. However, the signaling pathway for this function of SCF/c-kit has not been elucidated. We now demonstrate that SCF activates phosphoinositide 3-kinase (P13-K) and p70 S6 kinase (p70S6K) and that rapamycin, a FRAP/mammalian target of rapamycin-dependent inhibitor of p70S6K, completely inhibited bromodeoxyuridine incorporation induced by SCF in primary cultures of spermatogonia, SCF induced cyclin D3 expression and phosphorylation of the retinoblastoma protein through a pathway that is sensitive to both wortmannin and rapamycin, Furthermore, AKT, but not protein kinase C-zeta is used by SCF/c-kit/P13-K to activate p70S6K, Dominant negative AKT-K179M: completely abolished p70S6K phosphorylation induced by the constitutively active P13-K catalytic subunit p110, Constitutively active v-AKT highly phosphorylated p70S6K, which was totally inhibited by rapamycin, Thus, SCF/c-kit uses a rapamycin-sensitive P13-K/AKT/p70S6K/cyclin D3 pathway to promote spermatogonial cell proliferation.