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

Akiko Joo1, Hiroyuki Aburatani, Eiichi Morii

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

Oncogene
|January 23, 2004
PubMed

Insights

Microphthalmia-associated transcription factor (MITF) cooperates with Signal Transducer and Activator of Transcription 3 (STAT3) to promote cancer cell transformation. This partnership enhances c-fos expression, driving tumorigenesis and anchorage-independent growth.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Biology

Background:

  • Signal transducer and activator of transcription (STAT) proteins, particularly STAT3, are crucial in cytokine signaling and frequently activated in human cancers, contributing to tumorigenesis.
  • Constitutively activated STAT3 mutants (STAT3C) can induce cellular transformation, but their transformation potential is limited compared to oncogenes like v-src.
  • Identifying co-factors that enhance STAT3-mediated transformation is essential for understanding cancer development.

Purpose of the Study:

  • To identify novel tumorigenic factors that cooperate with STAT3C to induce cellular transformation.
  • To elucidate the molecular mechanisms underlying STAT3C- and MITF-mediated cellular transformation.

Main Methods:

  • Screening of a retroviral cDNA library to identify cooperating factors for STAT3C.
  • Soft-agar colony formation assays to assess anchorage-independent growth.
  • Microarray analysis to identify gene expression changes.
  • Promoter analysis and chromatin immunoprecipitation (ChIP) assays to investigate gene regulation.
  • Retroviral expression of dominant-negative AP-1 to assess the role of AP-1 in transformation.

Main Results:

  • Microphthalmia-associated transcription factor (MITF) was identified as a factor that cooperates with STAT3C to induce anchorage-independent growth in NIH-3T3 cells.
  • Microarray analysis revealed significant upregulation of c-fos in cells expressing both STAT3C and MITF.
  • STAT3 and MITF were shown to cooperatively upregulate c-fos expression via promoter activity and ChIP assays.
  • The transformation induced by MITF and STAT3C was significantly inhibited by a dominant-negative AP-1 retrovirus, highlighting AP-1's role.

Conclusions:

  • MITF collaborates with STAT3 to induce cellular transformation, characterized by anchorage-independent growth.
  • The cooperative action of MITF and STAT3 leads to the upregulation of c-fos, a key mediator of this transformation.
  • The AP-1 transcription factor complex plays a critical role in the MITF- and STAT3-driven cellular transformation process.

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