Deregulated expression of CDK2- or CDK3-associated kinase activities enhances c-Myc-induced apoptosis

被引:9
作者
Braun, K [1 ]
Hölzl, G [1 ]
Pusch, O [1 ]
Hengstschläger, M [1 ]
机构
[1] Univ Vienna, Dept Prenatal Diag & Therapy, A-1090 Vienna, Austria
关键词
D O I
10.1089/dna.1998.17.789
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
Activation of high ectopic levels of c-Myc in serum-deprived Rat1-MycER cells by 4-hydroxytamoxifen induces both proliferation and apoptosis, To further elucidate the role of G(1) cyclin-dependent kinases (CDKs) in the process of MSc-induced apoptosis, we generated Ratl-MycER cells stably overexpressing CDK2 or CDK3, Ectopic expression of these CDKs in Myc-overexpressing cells was accompanied by upregulation of the specific kinase activities. Whereas neither high ectopic CDK2 nor CDK3 alone induced apoptosis in serum-deprived Rat1 cells, both CDKs markedly elevated the incidence of Myc-induced apoptosis, It was shown earlier that in Rat1-MycER cells, which are resistant to tumor necrosis factor-alpha (TNF) when grown in high serum concentrations, the addition of TNF with the concomitant activation of Myc resulted in apoptotic cell death. Here, we show that neither CDK2 nor CDK3 induces susceptibility to the cytotoxic action of TNF in Rat1 cells. However, both molecules heavily elevated the incidence of apoptosis induced by TNF together with Myc. It has earlier been reported that Myc-induced apoptosis in serum-deprived Rat1 fibroblasts is inhibited by specific cytokines, such as platelet-derived growth factor (PDGF). Here, we demonstrate that PDGF-mediated protection from Myc-induced apoptosis is almost lost in Rat1 cells overexpressing CDK2 or CDK3. These apoptotic effects of CDK2 or CDK3 are not accompanied by alterations of proliferation parameters, such as DNA distribution, time the cells spend in each phase of the cell cycle, thymidine incorporation into DNA, or cell size analyzed during Myc-induced apoptosis. However, we found CDK3 to deregulate E2F-dependent transcription. In this report, we provide evidence for a not yet described property of CDK2 or CDK3 besides their activity in promoting proliferation: these G(1)-CDKs can promote apoptosis by interfering with the cell's response to survival factors.
引用
收藏
页码:789 / 798
页数:10
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共 55 条
  • [1] Cyclin E and c-Myc promote cell proliferation in the presence of p16(INK4a) and of hypophosphorylated retinoblastoma family proteins
    Alevizopoulos, K
    Vlach, J
    Hennecke, S
    Amati, B
    [J]. EMBO JOURNAL, 1997, 16 (17) : 5322 - 5333
  • [2] MYC-MAX-MAD - A TRANSCRIPTION FACTOR NETWORK CONTROLLING CELL-CYCLE PROGRESSION, DIFFERENTIATION AND DEATH
    AMATI, B
    LAND, H
    [J]. CURRENT OPINION IN GENETICS & DEVELOPMENT, 1994, 4 (01) : 102 - 108
  • [3] TRANSCRIPTIONAL ACTIVATION BY THE HUMAN C-MYC ONCOPROTEIN IN YEAST REQUIRES INTERACTION WITH MAX
    AMATI, B
    DALTON, S
    BROOKS, MW
    LITTLEWOOD, TD
    EVAN, GI
    LAND, H
    [J]. NATURE, 1992, 359 (6394) : 423 - 426
  • [4] SEQUENCE-SPECIFIC TRANSCRIPTIONAL ACTIVATION BY MYC AND REPRESSION BY MAX
    AMIN, C
    WAGNER, AJ
    HAY, N
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1993, 13 (01) : 383 - 390
  • [5] MAD-MAX TRANSCRIPTIONAL REPRESSION IS MEDIATED BY TERNARY COMPLEX-FORMATION WITH MAMMALIAN HOMOLOGS OF YEAST REPRESSOR SIN3
    AYER, DE
    LAWRENCE, QA
    EISENMAN, RN
    [J]. CELL, 1995, 80 (05) : 767 - 776
  • [6] MAD - A HETERODIMERIC PARTNER FOR MAX THAT ANTAGONIZES MYC TRANSCRIPTIONAL ACTIVITY
    AYER, DE
    KRETZNER, L
    EISENMAN, RN
    [J]. CELL, 1993, 72 (02) : 211 - 222
  • [7] INTERACTION OF C-MYC WITH THE PRB-RELATED PROTEIN P107 RESULTS IN INHIBITION OF C-MYC-MEDIATED TRANSACTIVATION
    BEIJERSBERGEN, RL
    HIJMANS, EM
    ZHU, L
    BERNARDS, R
    [J]. EMBO JOURNAL, 1994, 13 (17) : 4080 - 4086
  • [8] Cell cycle regulation by the retinoblastoma family of growth inhibitory proteins
    Beijersbergen, RL
    Bernards, R
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER, 1996, 1287 (2-3): : 103 - 120
  • [9] TRANSCRIPTIONAL REGULATION - FLIPPING THE MYC SWITCH
    BERNARDS, R
    [J]. CURRENT BIOLOGY, 1995, 5 (08) : 859 - 861
  • [10] SEQUENCE-SPECIFIC DNA-BINDING BY THE C-MYC PROTEIN
    BLACKWELL, TK
    KRETZNER, L
    BLACKWOOD, EM
    EISENMAN, RN
    WEINTRAUB, H
    [J]. SCIENCE, 1990, 250 (4984) : 1149 - 1151