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Akt phosphorylates and suppresses the transactivation of retinoic acid receptor alpha

Harish Srinivas1, Dianren Xia, Nicole L Moore

  • 1Department of Thoracic/Head and Neck Medical Oncology, Unit 432, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.

The Biochemical Journal
|January 19, 2006
PubMed

Insights

Akt-mediated phosphorylation of retinoic acid receptor alpha (RARalpha) inhibits its function, contributing to retinoid resistance in non-small cell lung cancer (NSCLC) cells.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Signaling

Background:

  • Nuclear receptor transactivation is modulated by ligand binding and phosphorylation.
  • Retinoic acid receptor alpha (RARalpha) phosphorylation by c-Jun N-terminal kinase is linked to retinoid resistance in some non-small cell lung cancer (NSCLC) cells.
  • The full mechanisms of retinoid resistance in NSCLC remain incompletely understood.

Purpose of the Study:

  • To investigate the role of Akt in RARalpha regulation and retinoid resistance in NSCLC.
  • To elucidate the molecular mechanisms by which Akt affects RARalpha activity.

Main Methods:

  • Biochemical assays to assess Akt-RARalpha interaction and phosphorylation.
  • Functional analyses using site-directed mutagenesis (Ser96 to alanine).
  • Experiments involving overexpression of dominant-negative Akt in NSCLC cell lines.

Main Results:

  • Constitutively active Akt phosphorylates RARalpha at Ser96 within its DNA-binding domain.
  • Akt-mediated phosphorylation inhibits RARalpha transactivation.
  • Mutating Ser96 to alanine prevents Akt from suppressing RARalpha activity.
  • Inhibition of Akt signaling in NSCLC cells reduces RARalpha phosphorylation, enhances RARalpha transactivation, and sensitizes cells to RAR ligand treatment.

Conclusions:

  • Akt signaling pathway contributes to retinoid resistance in a subset of NSCLC.
  • Akt-mediated inhibition of RARalpha transactivation is a key mechanism underlying this resistance.

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