Gemma A, Takenoshita S, Hagiwara K, Okamoto A, Spillare E A, McMemamin M G, Hussain S P, Forrester K, Zariwala M, Xiong Y, Harris C C
Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA.
Int J Cancer. 1996 Nov 27;68(5):605-11. doi: 10.1002/(SICI)1097-0215(19961127)68:5<605::AID-IJC9>3.0.CO;2-2.
Cyclin-dependent kinase-4 inhibitor genes (INK4) regulate the cell cycle and are candidate tumor-suppressor genes. To determine if alterations in the coding regions of the p18 and p19 genes, which are novel members of the INK4 family and if they correlate with the development of human cancer, 100 human cancer cell lines were analyzed. Two other INK4 gene family members, p15INK4b/MTS2 and p16INK4/MTS1 genes were also analyzed. Homozygous deletions of the p15INK4b/MTS2 gene were detected in 29 cancer cell lines. Thirty-five homozygous deletions and 7 intragenic mutations of the pl6INK4/MTS1 gene were also detected in these cell lines. Neither homozygous deletions nor intragenic mutations of the p18 and p19 genes were found except in an ovarian cancer cell line, SKOV3, harboring a single base pair deletion in exon 1 of p19. In p16INK4/MTS1 expression analysis, 5 cell lines with both authentic and alternative spliced p16INK4/MTS1 mRNA had no detectable p16INK4/MTS1 protein. These results suggest the hypotheses that either post-translational modification or enhanced degradation may be responsible for the lack of detection of the p16INK4/MTS1 protein. Using Western blot analysis, subsets of 26 human cancer cell lines were examined for p18 expression and 39 cell lines for p19 expression. All of these cell lines expressed the p18 or p19 protein, with the exception of SKOV3, which did not express p19. Therefore, the INK4 gene family may be divided into 2 groups. One group includes p15INK4b/MTS2 and p16INK4/MTS1, in which genetic and epigenetic alterations might contribute to the development of human cancers. The other group includes p18 and p19, in which somatic mutations are uncommon in many types of human cancer, and their role in human carcinogenesis and cancer progression is uncertain.
细胞周期蛋白依赖性激酶4抑制基因（INK4）调控细胞周期，是候选肿瘤抑制基因。为了确定INK4家族新成员p18和p19基因编码区的改变情况以及它们是否与人类癌症的发生相关，我们分析了100个人类癌细胞系。另外两个INK4基因家族成员，p15INK4b/MTS2和p16INK4/MTS1基因也进行了分析。在29个癌细胞系中检测到p15INK4b/MTS2基因的纯合缺失。在这些细胞系中还检测到35个p16INK4/MTS1基因的纯合缺失和7个基因内突变。除了在一个卵巢癌细胞系SKOV3中发现p19基因外显子1有一个单碱基对缺失外，未发现p18和p19基因的纯合缺失或基因内突变。在p16INK4/MTS1表达分析中，5个同时具有真实和可变剪接的p16INK4/MTS1 mRNA的细胞系未检测到p16INK4/MTS1蛋白。这些结果提示了这样的假说，即翻译后修饰或增强的降解可能是导致未检测到p16INK4/MTS1蛋白的原因。使用蛋白质印迹分析，对26个人类癌细胞系的亚组检测了p18表达，对39个细胞系检测了p19表达。除了不表达p19的SKOV3外，所有这些细胞系都表达p18或p19蛋白。因此，INK4基因家族可能分为两组。一组包括p15INK4b/MTS2和p16INK4/MTS1，其中遗传和表观遗传改变可能促成人类癌症的发生。另一组包括p18和p19，在许多类型的人类癌症中体细胞突变并不常见，它们在人类致癌作用和癌症进展中的作用尚不确定。
