Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3
Cyclin D1 is transcriptionally regulated by and required for transformation by activated signal transducer and activator of transcription 3
复制标题
DOI：
10.1158/0008-5472.can-05-2203
复制
发表时间：
2006-03-01
期刊：
影响因子：
11.2
通讯作者：
Bromberg, J
中科院分区：
文献类型：
--
作者：
Leslie, K;Lang, C;Bromberg, J
信号转导和转录激活因子3(STAT3)是一种转录因子，在许多癌细胞中被异常激活。结构性激活的STAT3是致癌的，可能是因为它对不同的基因进行了差异调节。在原发乳腺肿瘤和乳腺癌来源的细胞系中，激活的STAT3与细胞周期蛋白D1蛋白的升高相关。在表达STAT3致癌变异体(STAT3-C)或vSrc的原代大鼠、小鼠和人类来源的细胞系中，细胞周期蛋白D1mRNA水平升高，vSrc构成了STAT3的磷酸化。细胞周期蛋白D1启动子中STAT3结合位点的突变和染色质免疫沉淀研究表明，STAT3与人细胞周期蛋白D1基因的转录调控有关。将STAT3-C和vSrc导入永生化细胞周期蛋白D_1(-/-)和细胞周期蛋白D_1(-/-)后，只有细胞周期蛋白D_1(-/+)不依赖于锚定生长。此外，乳腺癌细胞中细胞周期蛋白D1的下调导致了锚定非依赖性生长的减少。在细胞周期蛋白D1(-/-)细胞中，视网膜母细胞瘤(Rb)蛋白的磷酸化相对细胞周期蛋白D1(-/+)延迟。E7癌基因的活性包括Rb的降解和Rb从E2F的解离，它不能赋予细胞周期蛋白D1(-/-)细胞独立于锚定的生长，但与vSrc结合，导致软琼脂中的强劲生长。这些结果表明，细胞周期蛋白D1在调控不同癌基因的转化过程中既有cdk依赖的作用，也有cdk不依赖的作用。
Signal transducers and activators of transcription 3 (STAT3) is a transcription factor that is aberrantly activated in many cancer cells. Constitutively activated STAT3 is oncogenic, presumably as a consequence of the genes that it differentially regulates. Activated STAT3 correlated with elevated cyclin D1 protein in primary breast tumors and breast cancer-derived cell lines. Cyclin D1 mRNA levels were increased in primary rat-, mouse-, and human-derived cell lines expressing either the oncogenic variant of STAT3 (STAT3-C) or vSrc, which constitutively phosphorylates STAT3. Mutagenesis of STAT3 binding sites within the cyclin D1 promoter and chromatin immunoprecipitation studies showed an association between STAT3 and the transcriptional regulation of the human cyclin D1 gene. Introduction of STAT3-C and vSrc into immortalized cyclin D1(-/-) and cyclin D1(-/-) fibroblasts led to anchorage-independent growth of only cyclin D1(-/+) cells. Furthermore, knockdown of cyclin D1 in breast carcinoma cells led to a reduction in anchorage-independent growth. Phosphorylation of the retinoblastoma (Rb) protein [a target of the cyclin D1/cyclin-dependent kinase 4/6 (cdk4/6) holoenzyme] was delayed in the cyclin D1(-/-) cells relative to cyclin D1(-/+) cells. The E7 oncogene, whose activity includes degradation of Rb and dissociation of Rb from E2F, did not confer anchorage-independent growth to the cyclin D1(-/-) cells but, in conjunction with vSrc, resulted in robust growth in soft agar. These results suggest both a cdk-dependent and cdk-independent role for cyclin D1 in modulating transformation by different oncogenes.