Effects of guanine nucleotide depletion on cell cycle progression in human T lymphocytes
Effects of guanine nucleotide depletion on cell cycle progression in human T lymphocytes
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DOI：
10.1182/blood.v91.8.2896.2896_2896_2904
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发表时间：
1998-04-15
期刊：
影响因子：
20.3
通讯作者：
Mitchell, BS
中科院分区：
文献类型：
--
作者：
Laliberté, J;Yee, A;Mitchell, BS
在抑制肌苷一磷酸脱氢酶（IMPDH）后，鸟嘌呤核苷酸库的耗尽通过将细胞阻滞在G1期而有效地抑制DNA合成，并且已经显示诱导培养的髓系和红系细胞系以及在原始细胞转化后的慢性粒细胞白血病细胞的分化。IMPDH的抑制剂作为免疫抑制剂也是高度有效的。鸟嘌呤核苷酸耗竭的多效性作用的机制尚不清楚。我们研究了霉酚酸（MPA），一种有效的IMPDH抑制剂，对活化的正常人T淋巴细胞的细胞周期进程的影响。MPA处理导致pRb磷酸化和细胞进入S期的抑制。细胞周期蛋白D3的表达，pRb磷酸化所需的细胞周期蛋白依赖性激酶（CDK）活性的主要组成部分，被完全废除的MPA治疗的T细胞活化的白细胞介素-2（IL-2）和白细胞凝集素（PHA-L），而细胞周期蛋白D2，CDK 6和CDK 4的表达更温和衰减。此外，MPA阻止了IL-2诱导的CDK抑制剂p27（Kip 1）的消除，并导致高水平的p27（Kip 1）在IL-2/PHA-L处理的与CDK 2结合的T细胞中保留。这些结果表明，从头合成的鸟嘌呤核苷酸的抑制阻断正常外周血T淋巴细胞从G 0到S期的早期到中期G1的过渡，这种细胞周期阻滞的结果从抑制诱导细胞周期蛋白D/CDK 6激酶和消除p27（Kip 1）抑制活性。(C)1998年，美国血液学会。
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.