Quelle D E, Ashmun R A, Hannon G J, Rehberger P A, Trono D, Richter K H, Walker C, Beach D, Sherr C J, Serrano M
Howard Hughes Medical Institute, Memphis, Tennessee, USA.
Oncogene. 1995 Aug 17;11(4):635-45.
Progression through the G1 phase of the cell cycle is regulated in part by the D-type cyclin-dependent kinases, cdk4 and cdk6. Genes encoding two specific inhibitors of these kinases, human p16(INK4a/MTS1) and p15(INK4b/MTS2), map to a region of common cytogenetic abnormalities on chromosome 9p21. The murine cognates of these genes were isolated and identified as mouse p16INK4a and p15INK4b based on their homology to their human counterparts and their selective transcriptional induction by SV40T-antigen and TGF-beta, respectively. Both genes map to position C3-C6 on mouse chromosome 4, in a region syntenic with human chromosome 9p. Amplification of polyadenylated mRNA by polymerase chain reactions revealed no expression of mouse p16INK4a in many normal tissues, whereas p15INK4b was expressed ubiquitously. Like human p16INK4a, mouse p16INK4a binds specifically to cdk4 and cdk6 in vitro and inhibits the phosphorylation of the retinoblastoma protein, pRb, by each of these cyclin D-dependent kinases. In mouse MEL erythroleukemia cells, p16INK4a associates preferentially with cdk6 under conditions where cdk4 and cdk6 are coexpressed at equivalent levels. Expression vectors encoding human or mouse p16INK4a caused G1 phase arrest in NIH3T3 fibroblasts, and cyclin D1- and cdk4-dependent pRb kinase activities were inhibited in the p16INK4a-arrested cells.
细胞周期G1期的进程部分受D型细胞周期蛋白依赖性激酶cdk4和cdk6调控。编码这两种激酶的两种特异性抑制剂的基因，即人类p16(INK4a/MTS1)和p15(INK4b/MTS2)，定位于9号染色体p21区域常见的细胞遗传学异常区域。基于它们与人类对应物的同源性以及分别被SV40T抗原和转化生长因子β选择性转录诱导，分离并鉴定了这些基因的小鼠同源物，分别为小鼠p16INK4a和p15INK4b。这两个基因都定位于小鼠4号染色体的C3 - C6位置，该区域与人类9号染色体p区域同线。通过聚合酶链反应扩增聚腺苷酸化mRNA发现，在许多正常组织中未检测到小鼠p16INK4a的表达，而p15INK4b则普遍表达。与人类p16INK4a一样，小鼠p16INK4a在体外能特异性结合cdk4和cdk6，并抑制这些细胞周期蛋白D依赖性激酶对视网膜母细胞瘤蛋白pRb的磷酸化。在小鼠MEL红白血病细胞中，当cdk4和cdk6以同等水平共表达时，p16INK4a优先与cdk6结合。编码人类或小鼠p16INK4a的表达载体可使NIH3T3成纤维细胞停滞于G1期，在p16INK4a停滞的细胞中，细胞周期蛋白D1和cdk4依赖性的pRb激酶活性受到抑制。
