Okamoto A, Demetrick D J, Spillare E A, Hagiwara K, Hussain S P, Bennett W P, Forrester K, Gerwin B, Serrano M, Beach D H
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11045-9. doi: 10.1073/pnas.91.23.11045.
Cell cycle arrest at the G1 checkpoint allows completion of critical macromolecular events prior to S phase. Regulators of the G1 checkpoint include an inhibitor of cyclin-dependent kinase, p16INK4; two tumor-suppressor proteins, p53 and RB (the product of the retinoblastoma-susceptibility gene); and cyclin D1. Neither p16INK4 nor the RB protein was detected in 28 of 29 tumor cell lines from human lung, esophagus, liver, colon, and pancreas. The presence of p16INK4 protein is inversely correlated with detectable RB or cyclin D1 proteins and is not correlated with p53 mutations. Homozygous deletions of p16INK4 were detected in several cell lines, but intragenic mutations of this gene were unusual in either cell lines or primary tumors. Transfection of the p16INK4 cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16INK4 expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16INK4 is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G1 checkpoint can lead to both escape from senescence and cancer formation.
细胞周期在G1检查点停滞，使得关键的大分子事件能够在S期之前完成。G1检查点的调节因子包括细胞周期蛋白依赖性激酶抑制剂p16INK4；两种肿瘤抑制蛋白p53和RB（视网膜母细胞瘤易感基因的产物）；以及细胞周期蛋白D1。在来自人肺、食管、肝、结肠和胰腺的29个肿瘤细胞系中的28个中，未检测到p16INK4和RB蛋白。p16INK4蛋白的存在与可检测到的RB或细胞周期蛋白D1蛋白呈负相关，且与p53突变无关。在几个细胞系中检测到p16INK4的纯合缺失，但该基因的基因内突变在细胞系或原发性肿瘤中均不常见。将p16INK4 cDNA表达载体转染到癌细胞中会抑制其集落形成效率，并且在体外持续传代时，表达p16INK4的细胞会被淘汰。这些结果与以下假设一致：p16INK4是一种肿瘤抑制蛋白，并且控制G1检查点的基因中的遗传和表观遗传异常可导致细胞逃脱衰老并形成癌症。
