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

Oncogene volume 23, pages 726–734 (2004)Cite this article

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 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.

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Acknowledgements

We thank Dr T Yoshida (Kurume University) for STAT3C-3T3, Dr Yonemitsu (Kyushu University) for melanoma cell lines, H Meguro for oligonucleotide microarray analysis, Y Kawabata for technical assistance, and N Arifuku for manuscript preparation. This work was supported by special grants-in-aid from the Ministry of Education, Science, Technology, Sports, and Culture of Japan, the Japan Health Science Foundation, the Human Frontier Science Program, the Japan Research Foundation for Clinical Pharmacology, Haraguchi Memorial foundation, and the Uehara Memorial Foundation. AJ is supported by the fellowship from Japan Society for Promotion of Science.

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Authors and Affiliations

  1. Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Akiko Joo & Akihiko Yoshimura

  2. Division of Genome Science, Research Center for Advanced Science and Technology, The University of Tokyo, Komaba, Meguro-ku, Tokyo, 153-8904, Japan

    Hiroyuki Aburatani

  3. Department of Pathology, Osaka University Medical School, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Eiichi Morii

  4. Institute of Medical Science, The University of Tokyo, Shirokane-dai, Minato-ku, Tokyo, 108-8639, Japan

    Hideo Iba

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  1. Akiko Joo
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Correspondence to Akihiko Yoshimura.

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Joo, A., Aburatani, H., Morii, E. et al. STAT3 and MITF cooperatively induce cellular transformation through upregulation of c-fos expression. Oncogene 23, 726–734 (2004). https://doi.org/10.1038/sj.onc.1207174

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