Dominant negative c-jun inhibits activation of the cyclin D1 and cyclin E kinase complexes

被引:44
作者
Hennigan, RF [1 ]
Stambrook, PJ [1 ]
机构
[1] Univ Cincinnati, Coll Med, Dept Cell Biol Neurobiol & Anat, Cincinnati, OH 45267 USA
关键词
D O I
10.1091/mbc.12.8.2352
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The AP-1 transcription factor is activated by oncogenic signal transduction cascades and its function is critical for both mitogenesis and carcinogenesis. To define the role of AP-1 in the context of a human fibrosarcoma cell line, HT1080, we expressed a dominant negative c-jun mutant fused to the green fluorescent protein in an ecdysone-inducible system. We demonstrated that high levels of this mutant, GFP-TAM67, inhibit AP-1 activity and arrest cells predominately in the G1 phase of the cell cycle. This arrest is reversible and occurs only above a threshold concentration; low to moderate levels of GFP-TAM67 are insufficient for growth arrest. Contrary to expectations based on the literature, GFP-TAM67 does not inhibit expression of cyclin DI, cyclin E, or their respective cyclin-dependent kinases. However, pRB is hypophosphorylated in GFP-TAM67-arrested cells and the activity of both the cyclin D1:cdk and the cyclin E:cdk complexes are impaired. Both of these complexes show an increased association with p21(CIP1/WAF1), concomitantly with induction of the p21 mRNA by GFP-TAM67. These results suggest a novel function of AP-1 in the activation of the G1 cyclin:cdk complexes in human tumor cells by regulating the expression of the p21(CIP1/WAF1) gene.
引用
收藏
页码:2352 / 2363
页数:12
相关论文
共 44 条
  • [1] THE TRANSACTIVATING DOMAIN OF THE C-JUN PROTO-ONCOPROTEIN IS REQUIRED FOR COTRANSFORMATION OF RAT EMBRYO CELLS
    ALANI, R
    BROWN, P
    BINETRUY, B
    DOSAKA, H
    ROSENBERG, RK
    ANGEL, P
    KARIN, M
    BIRRER, MJ
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1991, 11 (12) : 6286 - 6295
  • [2] TRANSFORMING P21(RAS) MUTANTS AND C-ETS-2 ACTIVATE THE CYCLIN D1 PROMOTER THROUGH DISTINGUISHABLE REGIONS
    ALBANESE, C
    JOHNSON, J
    WATANABE, G
    EKLUND, N
    VU, D
    ARNOLD, A
    PESTELL, RG
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (40) : 23589 - 23597
  • [3] Cell cycle-dependent variations in c-Jun and JunB phosphorylation: a role in the control of cyclin D1 expression
    Bakiri, L
    Lallemand, D
    Bossy-Wetzel, E
    Yaniv, M
    [J]. EMBO JOURNAL, 2000, 19 (09) : 2056 - 2068
  • [4] BENBROOK DM, 1990, ONCOGENE, V5, P295
  • [5] Fos family members induce cell cycle entry by activating cyclin D1
    Brown, JR
    Nigh, E
    Lee, RJ
    Ye, H
    Thompson, MA
    Saudou, F
    Pestell, RG
    Greenberg, ME
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1998, 18 (09) : 5609 - 5619
  • [6] BROWN PH, 1994, ONCOGENE, V9, P791
  • [7] BROWN PH, 1993, ONCOGENE, V8, P877
  • [8] NEGATIVE TRANSCRIPTIONAL REGULATION OF THE INTERFERON-GAMMA PROMOTER BY GLUCOCORTICOIDS AND DOMINANT-NEGATIVE MUTANTS OF C-JUN
    CIPPITELLI, M
    SICA, A
    VIGGIANO, V
    YE, JP
    GHOSH, P
    BIRRER, MJ
    YOUNG, HA
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (21) : 12548 - 12556
  • [9] v-Jun overrides the mitogen dependence of S-phase entry by deregulating retinoblastoma protein phosphorylation and E2F-pocket protein interactions as a consequence of enhanced cyclin E-cdk2 catalytic activity
    Clark, W
    Black, EJ
    MacLaren, A
    Kruse, U
    LaThangue, N
    Vogt, PK
    Gillespie, DAF
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2000, 20 (07) : 2529 - 2542
  • [10] CROWE DL, 2000, MOL CELL BIOL RES CO, V4, P243