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JAB1 regulates unphosphorylated STAT3 DNA-binding activity through protein-protein interaction in human colon cancer

Arata Nishimoto1, Naruji Kugimiya, Toru Hosoyama

  • 1Department of Surgery and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan. anishimo@yamaguchi-u.ac.jp

Biochemical and Biophysical Research Communications
|August 6, 2013
PubMed

Insights

Jun activation domain-binding protein 1 (JAB1) positively regulates unphosphorylated STAT3 DNA binding in colon cancer cells. This interaction is crucial for activating STAT3 target genes involved in oncogenesis, offering potential new cancer drug targets.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Signal Transduction

Background:

  • Unphosphorylated STAT3 plays a role in oncogenesis by translocating to the nucleus and activating target genes.
  • Nuclear translocation and DNA binding are critical activation steps for unphosphorylated STAT3.
  • The precise mechanism of unphosphorylated STAT3 binding to target gene promoters is not fully understood.

Purpose of the Study:

  • To investigate the role of Jun activation domain-binding protein 1 (JAB1) in regulating the DNA-binding activity of unphosphorylated STAT3.
  • To elucidate the mechanism by which JAB1 influences unphosphorylated STAT3's function in colon cancer cells.

Main Methods:

  • Immunoprecipitation assays to detect protein-protein interactions between JAB1 and unphosphorylated STAT3 in nuclear extracts.
  • RNA interference (RNAi) to knock down JAB1 expression and assess its impact on STAT3 activity and target gene expression.
  • Comparative analysis of nuclear JAB1 and STAT3 levels with DNA-binding activity in different colon cancer cell lines (COLO205 and LoVo).

Main Results:

  • Both unphosphorylated STAT3 and JAB1 were found in the nucleus of COLO205 cells under basal conditions.
  • JAB1 directly interacted with unphosphorylated STAT3 in the nucleus.
  • JAB1 knockdown decreased unphosphorylated STAT3 DNA-binding activity and the expression of STAT3 target genes (MDR1, NANOG, VEGF).
  • Nuclear JAB1 levels correlated with unphosphorylated STAT3 DNA-binding activity.

Conclusions:

  • Nuclear JAB1 positively regulates the DNA-binding activity of unphosphorylated STAT3 through protein-protein interaction.
  • JAB1 is a key regulator of unphosphorylated STAT3-mediated transcription of oncogenic target genes in colon cancer.
  • Targeting the JAB1-STAT3 interaction could be a novel strategy for colon cancer therapy.
Keywords:
JAB1Protein–protein interactionSTAT3 DNA-binding activityUnphosphorylated STAT3

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