Lukas J, Aagaard L, Strauss M, Bartek J
Danish Cancer Society, Division of Cancer Biology, Copenhagen O, Denmark.
Cancer Res. 1995 Nov 1;55(21):4818-23.
The p16INK4/CDKN2, D-type cyclins, their partner cyclin-dependent kinases, and retinoblastoma protein constitute a G1 regulatory pathway commonly targeted in oncogenesis. We show that, unexpectedly, abnormalities of p16INK4/CDKN2 occur concomitantly in two-thirds of cancer cell lines harboring aberrations of cyclin D1. Gene and protein transfer experiments demonstrated that concurrent alterations of cyclin D1 and p16 levels cooperate to (de)regulate G1 control in diploid fibroblasts, and that both events influence growth of retinoblastoma (RB)-positive, but not RB-deficient cancer cells. These results show that biological consequences of deregulating individual components along the pathway are unequal, reflecting their hierarchical roles in the G1 checkpoint control. Whereas RB defects eliminate the checkpoint completely, aberrations of the upstream components, such as cyclin D1 and p16INK4/CDKN2, can cooperate in multistep tumorigenesis.
p16INK4/CDKN2、D型细胞周期蛋白、它们的伙伴细胞周期蛋白依赖性激酶以及视网膜母细胞瘤蛋白构成了一条在肿瘤发生过程中常被靶向的G1调控通路。我们意外地发现，在三分之二携带细胞周期蛋白D1畸变的癌细胞系中，p16INK4/CDKN2同时出现异常。基因和蛋白质转移实验表明，细胞周期蛋白D1和p16水平的同时改变协同作用于（去）调节二倍体成纤维细胞中的G1控制，并且这两个事件都影响视网膜母细胞瘤（RB）阳性而非RB缺陷癌细胞的生长。这些结果表明，该通路中各个成分失调的生物学后果并不相同，这反映了它们在G1检查点控制中的层级作用。RB缺陷会完全消除检查点，而上游成分如细胞周期蛋白D1和p16INK4/CDKN2的畸变则可在多步骤肿瘤发生过程中协同作用。
