CDK6 blocks differentiation: coupling cell proliferation to the block to differentiation in leukemic cells
CDK6 blocks differentiation: coupling cell proliferation to the block to differentiation in leukemic cells
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DOI：
10.1038/sj.onc.1206484
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发表时间：
2003-07-03
期刊：
影响因子：
8
通讯作者：
Skoultchi, AI
中科院分区：
文献类型：
--
作者：
Matushansky, I;Radparvar, F;Skoultchi, AI
在正常发育过程中，细胞增殖和分化是高度协调的。许多肿瘤细胞表现出不受控制的增殖和终末分化受阻。为了了解协调这两个过程的机制，我们研究了细胞周期蛋白依赖性激酶（CDK）活性与鼠红白血病（MEL）细胞分化阻断之间的关系。我们发现，当 MEL 细胞被诱导重新进入红系分化时，CDK6（但不是 CDK4）迅速下调，并且通过转染维持 CDK6（但不是 CDK4）活性会阻止分化。此外，我们发现 PU.1（一种 Ets 转录因子）在红系细胞中具有致癌性，也可以阻止其分化，控制 CDK6 mRNA 的合成。这些结果表明，通过致癌转录因子 (PU.1) 对关键细胞周期调节因子 (CDK6) 的作用，将这些白血病细胞的增殖和分化阻断耦合起来。我们的研究结果表明，研究 CDK6 和 CDK4 在其他类型恶性细胞中的相对作用对于设计癌症细胞周期抑制和分化治疗方法非常重要。
Cell proliferation and differentiation are highly coordinated during normal development. Many tumor cells exhibit both uncontrolled proliferation and a block to terminal differentiation. To understand the mechanisms coordinating these two processes, we have investigated the relation between cyclin-dependent kinase (CDK) activities and the block to differentiation in murine erythroleukemia (MEL) cells. We found that CDK6 (but not CDK4) is rapidly downregulated as MEL cells are induced to re-enter erythroid differentiation and that maintenance of CDK6 (but not CDK4) activity by transfection blocks differentiation. Moreover, we found that PU.1, an Ets transcription factor that is oncogenic in erythroid cells and also can block their differentiation, controls the synthesis of CDK6 mRNA. These results suggest a mechanism for coupling proliferation and the block to differentiation in these leukemic cells through the action of an oncogenic transcription factor (PU.1) on a key cell cycle regulator (CDK6). Our findings suggest that studying the relative roles of CDK6 and CDK4 in other types of malignant cells will be important in designing approaches for cell cycle inhibition and differentiation therapy in cancer.