STAT3 and MITF cooperatively induce cellular transformation through upregulation of c-fos expression

Abstract

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 microphthalmiaassociated transcription factor (MITF), an essential transcription factor for melanocyte development and pigmentation, induces anchorage-independent growth of NIH-3T3 cells in cooperation with STAT3C. Microarray 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.

A Specific Epitope of Protein Inhibitor of Activated STAT3 Is Responsible for the Induction of Apoptosis in Rat Transformed Mast Cells

“…These predictions suggest a biological mechanism that regulates the expression PIAS3 82-132 via alternative splicing. The possible absent expression of PIAS3 82-132 by differential alternative splicing can potentially lead to a lack of regulation of MITF and STAT3 and even to cellular transformation (50). Furthermore, the optimized 23-aa fragment, PIAS3 82-104 , would seem to be have interesting and important biological potential.…”

Analysis of KRAP expression and localization, and genes regulated by KRAP in a human colon cancer cell line

“…The preparation of cytoplasmic and nuclear fractions was performed as described previously (Joo et al 2004).…”

LPS induces the interaction of a transcription factor, LPS-induced TNF-α factor, and STAT6(B) with effects on multiple cytokines

“…One explanation might be that because the TNF-␣ promoter contains not only the LITAF-binding site but also sites for NF-B, activating protein 1, and others (2-7), corresponding transcription factors can also be induced by LPS to bind to the TNF promoter and regulate its gene expression. Alternatively, in some cases, cytokine gene expression is regulated by cofactors that singly reduce promoter activity but together enhance it to a significant extent (10,11). Therefore, we hypothesized that LITAF might require the participation of a cofactor to substantially induce TNF-␣ gene expression.…”