Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas.
Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas.
复制标题
DOI：
--
复制
发表时间：
1993-11
期刊：
影响因子：
11.2
通讯作者：
Khatib Za;H. Matsushime;M. Valentine;D. Shapiro;C. Sherr;A. Look
中科院分区：
文献类型：
--
作者：
Khatib Za;H. Matsushime;M. Valentine;D. Shapiro;C. Sherr;A. Look
34千道尔顿周期蛋白依赖性激酶p34cdk4是哺乳动物d型周期蛋白的主要催化亚基，在细胞周期的G1期起作用，强制细胞进入S期的决定。利用小鼠互补DNA克隆克隆了人类CDK4同源基因，该基因定位于人类12号染色体q13带。由于这条染色体带包含GLI和MDM2基因，这两个基因在人类肉瘤中经常被扩增，我们分析了一组肉瘤细胞系中的CDK4拷贝数和表达。骨肉瘤细胞系OsACL的CDK4拷贝数增加了25倍，与GLI和MDM2的扩增一致，而横纹肌肉瘤细胞系SJRH30的扩增子包括CDK4和GLI，但不包括MDM2。CDK4 mRNA和蛋白在两种细胞系中均过表达，核苷酸测序分析表明该基因未发生持续突变。这些观察结果提供了编码细胞分裂周期蛋白激酶基因扩增的第一个证据，补充了最近的数据，表明编码d型细胞周期蛋白的基因是肿瘤细胞中染色体重排和基因扩增的目标，并表明CDK4扩增可能有助于肿瘤的发生。
The 34-kilodalton cyclin-dependent kinase, p34cdk4, is a major catalytic subunit of mammalian D-type cyclins, which act during the G1 phase of the cell cycle to enforce the decision of cells to enter S phase. A murine complementary DNA clone was used to clone the cognate human CDK4 gene, which was localized to human chromosome 12, band q13, by fluorescence in situ hybridization. Because this chromosomal band contains the GLI and MDM2 genes, which are frequently amplified in human sarcomas, we analyzed CDK4 copy number and expression in a panel of sarcoma cell lines. An osteosarcoma cell line, OsACL, manifested a 25-fold increased copy number of CDK4, amplified concordantly with both GLI and MDM2, whereas a rhabdomyosarcoma cell line, SJRH30, was found to have an amplicon that included CDK4 and GLI but not MDM2. CDK4 mRNA and protein were overexpressed in both cell lines, and nucleotide sequencing analysis indicated that the gene had not sustained mutations. These observations provide the first evidence for amplification of a gene encoding a cell division cycle protein kinase, complement recent data indicating that genes encoding D-type cyclins are targets of chromosomal rearrangement and gene amplification in tumor cells, and suggest that CDK4 amplification might contribute to oncogenesis.