STAT3 and MITF cooperatively induce cellular transformation through upregulation of c-fos expression.
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. 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.
Joo
Akiko
A
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Aburatani
Hiroyuki
H
Morii
Eiichi
E
Iba
Hideo
H
Yoshimura
Akihiko
A
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D016762:Genes, fos; D006801:Humans; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*
D017931:DNA Primers; D004268:DNA-Binding Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors