Effects of guanine nucleotide depletion on cell cycle progression in human T lymphocytes

被引:95
作者
Laliberté, J
Yee, A
Xiong, Y
Mitchell, BS [1 ]
机构
[1] Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Pharmacol, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, Dept Biochem, Chapel Hill, NC 27599 USA
[3] Univ N Carolina, Dept Biophys, Chapel Hill, NC USA
[4] Univ N Carolina, Dept Med, Chapel Hill, NC USA
[5] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
关键词
D O I
10.1182/blood.V91.8.2896.2896_2896_2904
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Depletion of guanine nucleotide pools after inhibition of inosine monophosphate dehydrogenase (IMPDH) potently inhibits DNA synthesis by arresting cells in G1 and has been shown to induce the differentiation of cultured myeloid and erythroid cell lines, as well as chronic granulocytic leukemic cells after blast transformation, Inhibitors of IMPDH are also highly effective as immunosuppressive agents. The mechanism underlying these pleiotropic effects of depletion of guanine nucleotides is unknown. We have examined the effects of mycophenolic acid (MPA), a potent IMPDH inhibitor, on the cell cycle progression of activated normal human T lymphocytes. MPA treatment resulted in the inhibition of pRb phosphorylation and cell entry into S phase. The expression of cyclin D3, a major component of the cyclin-dependent kinase (CDK) activity required for pRb phosphorylation, was completely abrogated by MPA treatment of T cells activated by interleukin-2 (IL-2) and leucoagglutinin (PHA-L), whereas the expression of cyclin D2, CDK6, and CDK4 was more mildly attenuated. The direct kinase activity of a complex immunoprecipitated with anti-CDK6 antibody was also inhibited, In addition, MPA prevented the IL-2-induced elimination of p27(Kip1), a CDK inhibitor, and resulted in the retention of high levels of p27(Kip1) in IL-2/PHA-L-treated T cells bound to CDK2. These results indicate that inhibition of the de novo synthesis of guanine nucleotides blocks the transition of normal peripheral blood T lymphocytes from G0 to S phase in early-to mid-G1 and that this cell cycle arrest results from inhibition of the induction of cyclin D/CDK6 kinase and the elimination of p27(Kip1) inhibitory activity. (C) 1998 by The American Society of Hematology.
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页码:2896 / 2904
页数:9
相关论文
共 52 条
  • [1] AJCHENBAUM F, 1993, J BIOL CHEM, V268, P4113
  • [2] Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27(KIP1)
    Aktas, H
    Cai, H
    Cooper, GM
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (07) : 3850 - 3857
  • [3] ALLISON AC, 1991, TRANSPL P, V23, P10
  • [4] CATAPANO CV, 1995, MOL PHARMACOL, V47, P948
  • [5] DAYTON JS, 1992, MOL PHARMACOL, V41, P671
  • [6] DUCLIC V, 1994, CELL, V76, P1013
  • [7] WAF1, A POTENTIAL MEDIATOR OF P53 TUMOR SUPPRESSION
    ELDEIRY, WS
    TOKINO, T
    VELCULESCU, VE
    LEVY, DB
    PARSONS, R
    TRENT, JM
    LIN, D
    MERCER, WE
    KINZLER, KW
    VOGELSTEIN, B
    [J]. CELL, 1993, 75 (04) : 817 - 825
  • [8] Cell cycle checkpoints: Preventing an identity crisis
    Elledge, SJ
    [J]. SCIENCE, 1996, 274 (5293) : 1664 - 1672
  • [9] p53 involves cytosine arabinoside-induced apoptosis in cultured cerebellar granule neurons
    Enokido, Y
    Araki, T
    Aizawa, S
    Hatanaka, H
    [J]. NEUROSCIENCE LETTERS, 1996, 203 (01) : 1 - 4
  • [10] FUNCTIONAL INTERACTIONS OF THE RETINOBLASTOMA PROTEIN WITH MAMMALIAN D-TYPE CYCLINS
    EWEN, ME
    SLUSS, HK
    SHERR, CJ
    MATSUSHIME, H
    KATO, JY
    LIVINGSTON, DM
    [J]. CELL, 1993, 73 (03) : 487 - 497