STAT3 and MITF cooperatively induce cellular transformation through upregulation of c-fos expression
STAT3 and MITF cooperatively induce cellular transformation through upregulation of c-fos expression
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DOI：
10.1038/sj.onc.1207174
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发表时间：
2004-01-22
期刊：
影响因子：
8
通讯作者：
Yoshimura, A
中科院分区：
文献类型：
--
作者：
Joo, A;Aburatani, H;Yoshimura, A
信号转导和转录激活因子(STAT)家族蛋白是介导细胞因子信号转导的关键转录因子。其中，STAT3在许多人类癌症和转化细胞系中经常被激活，并与肿瘤的发生有关。然而，尽管构成激活的STAT3突变体(STAT3C)会导致细胞转化，但其转化潜力，如在软琼脂中的集落形成活性，远远弱于v-src。为了确定与STAT3C协同诱导细胞转化的致瘤因子，我们筛选了逆转录病毒的cDNA文库。我们发现，小眼球相关转录因子(MITF)是黑素细胞发育和着色所必需的转录因子，它与STAT3C协同诱导NIH-3T3细胞非锚定生长。微阵列分析表明，c-fos在表达STAT3C和MITF的转化子中高度表达。启动子分析和染色质免疫沉淀分析表明，STAT3和MITF均能协同上调c-fos基因。此外，MITF和STAT3C对NIH-3T3细胞的转化均被显性阴性的AP-1逆转录病毒显著抑制。这些数据表明，MITF和STAT3协同诱导c-fos，导致细胞转化。
The signal transducer and activator of transcription ( STAT) family proteins are transcription factors critical in mediating cytokine signaling. Among them, STAT3 is frequently activated in a number of human cancers and transformed cell lines and is implicated in tumorigenesis. However, although constitutively activated STAT3 mutant (STAT3C) leads to cellular transformation, its transformation potential such as colony-forming activity in soft-agar is much weaker than that of v-src. To identify tumorigenic factors that cooperatively induce cellular transformation with STAT3C, we screened the retroviral cDNA library. We found that the microphthalmia-associated transcription factor ( MITF), an essential transcription factor for melanocyte development and pigmentation, induces anchorage-independent growth of NIH-3T3 cells in cooperation with STAT3C. Micro array analysis revealed that c-fos is highly expressed in transformants expressing STAT3C and MITF. Promoter analysis and chromatin immunoprecipitation assay suggested that both STAT3 and MITF can cooperatively upregulate the c-fos gene. In addition, the transformation of NIH-3T3 cells by both MITF and STAT3C was significantly suppressed by a dominant-negative AP-1 retrovirus. These data indicate that MITF and STAT3 cooperatively induce c-fos, resulting in cellular transformation.