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

被引:202
作者
Feng, LX [1 ]
Ravindranath, N [1 ]
Dym, M [1 ]
机构
[1] Georgetown Univ, Med Ctr, Dept Cell Biol, Washington, DC 20007 USA
关键词
D O I
10.1074/jbc.M002218200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:25572 / 25576
页数:5
相关论文
共 27 条
  • [1] Kit/stem cell factor receptor-induced activation of phosphatidylinositol 3′-kinase is essential for male fertility
    Blume-Jensen, P
    Jiang, GQ
    Hyman, R
    Lee, KF
    O'Gorman, S
    Hunter, T
    [J]. NATURE GENETICS, 2000, 24 (02) : 157 - 162
  • [2] PROTEIN-KINASE-B (C-AKT) IN PHOSPHATIDYLINOSITOL-3-OH INASE SIGNAL-TRANSDUCTION
    BURGERING, BMT
    COFFER, PJ
    [J]. NATURE, 1995, 376 (6541) : 599 - 602
  • [3] THE PROTO-ONCOGENE C-KIT ENCODING A TRANSMEMBRANE TYROSINE KINASE RECEPTOR MAPS TO THE MOUSE W-LOCUS
    CHABOT, B
    STEPHENSON, DA
    CHAPMAN, VM
    BESMER, P
    BERNSTEIN, A
    [J]. NATURE, 1988, 335 (6185) : 88 - 89
  • [4] THE 70-KDA S6-KINASE - REGULATION OF A KINASE WITH MULTIPLE ROLES IN MITOGENIC SIGNALING
    CHOU, MM
    BLENIS, J
    [J]. CURRENT OPINION IN CELL BIOLOGY, 1995, 7 (06) : 806 - 814
  • [5] DIRAMI G, 1996, ERNST SCHERING RES F, P141
  • [6] EXPRESSION OF C-KIT RECEPTOR AND ITS AUTOPHOSPHORYLATION IN IMMATURE RAT TYPE-A SPERMATOGONIA
    DYM, M
    JIA, MC
    DIRAMI, G
    PRICE, JM
    RABIN, SJ
    MOCCHETTI, I
    RAVINDRANATH, N
    [J]. BIOLOGY OF REPRODUCTION, 1995, 52 (01) : 8 - 19
  • [8] DYM M, 1983, HISTOLOGY CELL TISSU
  • [9] Multiple Ras effector pathways contribute to G1 cell cycle progression
    Gille, H
    Downward, J
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (31) : 22033 - 22040
  • [10] Grewe M, 1999, CANCER RES, V59, P3581