Regulation of signal transducer and activator of transcription 3 enhanceosome formation by apurinic/apyrimidinic endonuclease 1 in hepatic acute phase response

Sutapa Ray, Chang Lee, Tieying Hou, Kishor K. Bhakat, Allan R. Brasier

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The signal transducer and activator of transcription-3 (STAT3) is a latent IL-6 inducible transcription factor that mediates hepatic and vascular inflammation. In this study, we make the novel observation that STAT3 forms an inducible complex with the apurinic/apyrimidinic endonuclease 1 (APE1)/redox effector factor-1 (APE1/Ref-1), an essential multifunctional protein in DNA base excision repair, and studied the role of APE1/Ref-1 in STAT3 function. Using a transfection-coimmunoprecipitation assay, we observed that APE1 selectively binds the NH2-terminal acetylation domain of STAT3. Ectopic expression of APE1 potentiated inducible STAT3 reporter activity, whereas knockdown of APE1 resulted in reduced IL-6-inducible acute-phase reactant protein expression (C-reactive protein and serum amyloid P) and monocyte chemotactic protein-1 expression. The mechanism for APE1 requirement in IL-6 signaling was indicated by reduced STAT3 DNA binding activity observed in response to small interfering RNA-mediated APE1 silencing. Consistent with these in vitro studies,wealso observed that lipopolysaccharide-induced activation of acute-phase reactant protein expression is significantly abrogated in APE1 heterozygous mice compared with wild-type mice. IL-6 induces both STAT3 and APE1 to bind the suppressor of cytokine signaling-3 and γ-fibrionogen promoters in their native chromatin environment. Moreover, we observed that APE1 knockdown destabilized formation of the STAT3-inducible enhanceosome on the endogenous γ-fibrionogen promoter. Taken together, our study indicates that IL-6 induces a novel STAT3-APE1 complex, whose interaction is required for stable chromatin association in the IL-6-induced hepatic acute phase response.

Original languageEnglish (US)
Pages (from-to)391-401
Number of pages11
JournalMolecular Endocrinology
Volume24
Issue number2
DOIs
StatePublished - Feb 2010

Fingerprint

DNA-(Apurinic or Apyrimidinic Site) Lyase
STAT3 Transcription Factor
Acute-Phase Reaction
Endonucleases
Liver
Interleukin-6
Acute-Phase Proteins
Chromatin
Chemokine CCL2
DNA
Acetylation
Protein C
Amyloid
DNA Repair
C-Reactive Protein
Small Interfering RNA
Oxidation-Reduction
Transfection
Blood Vessels
Lipopolysaccharides

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Regulation of signal transducer and activator of transcription 3 enhanceosome formation by apurinic/apyrimidinic endonuclease 1 in hepatic acute phase response. / Ray, Sutapa; Lee, Chang; Hou, Tieying; Bhakat, Kishor K.; Brasier, Allan R.

In: Molecular Endocrinology, Vol. 24, No. 2, 02.2010, p. 391-401.

Research output: Contribution to journalArticle

Ray, Sutapa ; Lee, Chang ; Hou, Tieying ; Bhakat, Kishor K. ; Brasier, Allan R. / Regulation of signal transducer and activator of transcription 3 enhanceosome formation by apurinic/apyrimidinic endonuclease 1 in hepatic acute phase response. In: Molecular Endocrinology. 2010 ; Vol. 24, No. 2. pp. 391-401.
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