Zhou J N, Ljungdahl S, Röhme D, Levan G, Shoshan M C, Linder S
Department of Oncology and Pathology, Karolinska Institute and Hospital, Stockholm, Sweden.
Genes Chromosomes Cancer. 1997 Sep;20(1):82-9.
The cyclin kinase inhibitor p16, encoded by the CDKN2A gene, suppresses the transformation of mouse embryonic fibroblasts by oncogenic RAS. In contrast, the c-JUN transcription factor (a major component of AP-1) has been suggested to be required for RAS transformation of rodent fibroblasts. The CDKN2A gene and the JUN proto-oncogene have both been mapped to rat chromosome band 5q31-33. We here show that both copies of the CDKN2A gene are deleted in four of eight transformed cell lines derived from the transfection of rat embryo fibroblasts (REF) with HRASVAL12. In two cell lines, the homozygous deletions involved a larger area on 5q31-33, which included the JUN proto-oncogene. JUN-defective cells showed high AP-1 binding activity. Both AP-1 binding activity and stromelysin (transin) mRNA expression were found to be RAS-dependent in one of the JUN-defective cell lines. The finding of deletions of the CDKN2A gene in RAS-transformed REF cell lines is consistent with the concept that CDKN2A suppresses transformation by RAS. The occasional concomitant loss of the adjacent JUN proto-oncogene does not prevent establishment of transformed and tumorigenic cell lines.
由CDKN2A基因编码的细胞周期蛋白激酶抑制剂p16可抑制致癌性RAS诱导的小鼠胚胎成纤维细胞转化。相反，c-JUN转录因子（AP-1的主要成分）被认为是啮齿动物成纤维细胞RAS转化所必需的。CDKN2A基因和JUN原癌基因均已定位到大鼠染色体5q31-33带。我们在此表明，在通过HRASVAL12转染大鼠胚胎成纤维细胞（REF）获得的8个转化细胞系中的4个中，CDKN2A基因的两个拷贝均被缺失。在两个细胞系中，纯合缺失涉及5q31-33上更大的区域，其中包括JUN原癌基因。JUN缺陷型细胞显示出高AP-1结合活性。在其中一个JUN缺陷型细胞系中，发现AP-1结合活性和基质溶解素（转胶酶）mRNA表达均依赖于RAS。在RAS转化的REF细胞系中发现CDKN2A基因缺失，这与CDKN2A抑制RAS介导的转化这一概念一致。相邻的JUN原癌基因偶尔伴随缺失并不妨碍建立转化的和致瘤的细胞系。
