c-Jun N-terminal kinase contributes to aberrant retinoid signaling in lung cancer cells by phosphorylating and inducing proteasomal degradation of retinoic acid receptor α

Harish Srinivas, Denise M. Juroske, Shailaja Kalyankrishna, Dianna D. Cody, Roger E. Price, Xiao Chun Xu, Ramesh Narayanan, Nancy L. Weigel, Jonathan M. Kurie

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

Retinoic acid (RA) is the ligand for nuclear RA receptors (RARs and RXRs) and is crucial for normal epithelial cell growth and differentiation. During malignant transformation, human bronchial epithelial cells acquire a block in retinoid signaling caused in part by a transcriptional defect in RARs. Here, we show that activation of c-Jun N-terminal kinase (JNK) contributes to RAR dysfunction by phosphorylating RARα and inducing degradation through the ubiquitin-proteasomal pathway. Analysis of RARα mutants and phosphopeptide mapping revealed that RARα residues Thr181, Ser445, and Ser461 are phosphorylated by JNK. Mutation of these residues to alanines prevented efficient ubiquitination of RARα and increased the stability of the protein. We investigated the importance of RARα phosphorylation by JNK as a mediator of retinoid resistance in lung cancer. Mice that develop lung cancer from activation of a latent K-ras oncogene had high intratumoral JNK activity and low RARα levels and were resistant to treatment with an RAR ligand. JNK inhibition in a human lung cancer cell line enhanced RARα levels, ligand-induced activity of RXR-RAR dimers, and growth inhibition by RA. These findings point to JNK as a key mediator of aberrant retinoid signaling in lung cancer cells.

Original languageEnglish (US)
Pages (from-to)1054-1069
Number of pages16
JournalMolecular and cellular biology
Volume25
Issue number3
DOIs
StatePublished - Feb 1 2005

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Retinoic Acid Receptors
JNK Mitogen-Activated Protein Kinases
Retinoids
Lung Neoplasms
Ligands
Tretinoin
Epithelial Cells
Phosphopeptides
ras Genes
Protein Stability
Ubiquitination
Growth
Ubiquitin
Alanine
Cell Differentiation
Phosphorylation
Cell Line
Mutation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

c-Jun N-terminal kinase contributes to aberrant retinoid signaling in lung cancer cells by phosphorylating and inducing proteasomal degradation of retinoic acid receptor α. / Srinivas, Harish; Juroske, Denise M.; Kalyankrishna, Shailaja; Cody, Dianna D.; Price, Roger E.; Xu, Xiao Chun; Narayanan, Ramesh; Weigel, Nancy L.; Kurie, Jonathan M.

In: Molecular and cellular biology, Vol. 25, No. 3, 01.02.2005, p. 1054-1069.

Research output: Contribution to journalArticle

Srinivas, Harish ; Juroske, Denise M. ; Kalyankrishna, Shailaja ; Cody, Dianna D. ; Price, Roger E. ; Xu, Xiao Chun ; Narayanan, Ramesh ; Weigel, Nancy L. ; Kurie, Jonathan M. / c-Jun N-terminal kinase contributes to aberrant retinoid signaling in lung cancer cells by phosphorylating and inducing proteasomal degradation of retinoic acid receptor α. In: Molecular and cellular biology. 2005 ; Vol. 25, No. 3. pp. 1054-1069.
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