Grimison B, Langan T A, Sclafani R A
University of Colorado Comprehensive Cancer Center and Department of Biochemistry and Molecular Genetics, Denver 80262, USA.
Cell Growth Differ. 2000 Oct;11(10):507-15.
As cell cycle regulators whose activity is frequently altered in human cancers, cyclin-dependent kinases (cdks) are novel targets for therapeutic intervention. cdk inhibition is an emerging strategy for the treatment of non-small cell lung carcinomas (NSCLCs) because most derived cell lines express functional retinoblastoma protein (Rb) but appear to bypass its function with inappropriate cdk activity. Elevated cdk4/cdk6 activity in NSCLC cells is often due to inactivation of the p16Ink4a cdk inhibitor. To model the effects of cdk4/cdk6 inhibition, we have expressed p16Ink4a in a Rb-positive NSCLC cell line that lacks endogenous p16Ink4a expression. Whereas cdk4/cdk6 inhibition and Rb dephosphorylation are expected on p16Ink4a expression, we have also observed indirect cdk2 inhibition. cdk2 inactivation by the redistribution of other cdk inhibitors may be required for p16Ink4a-mediated growth suppression of Rb-positive cells. The implications of such a requirement on the use of chemical cdk inhibitors to treat human cancers will be discussed.
作为细胞周期调节因子，其活性在人类癌症中经常发生改变，细胞周期蛋白依赖性激酶（cdks）是治疗干预的新靶点。cdk抑制是治疗非小细胞肺癌（NSCLCs）的一种新兴策略，因为大多数衍生细胞系表达功能性视网膜母细胞瘤蛋白（Rb），但似乎通过不适当的cdk活性绕过其功能。NSCLC细胞中cdk4/cdk6活性升高通常是由于p16Ink4a cdk抑制剂失活。为了模拟cdk4/cdk6抑制的效果，我们在缺乏内源性p16Ink4a表达的Rb阳性NSCLC细胞系中表达了p16Ink4a。虽然预期p16Ink4a表达会导致cdk4/cdk6抑制和Rb去磷酸化，但我们也观察到间接的cdk2抑制。p16Ink4a介导的Rb阳性细胞生长抑制可能需要通过其他cdk抑制剂的重新分布来使cdk2失活。将讨论这种需求对使用化学cdk抑制剂治疗人类癌症的影响。
