Cited by 68Retinoids in leukemia and cellular processesPeroxisome Proliferator-Activated ReceptorsProtein Kinase Regulation and GTPase Signaling

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

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Srinivas, Harish, Juroske, Denise M., Kalyankrishna, Shailaja, Cody, Dianna D., Price, Roger E., Xu, Xiao-Chun, Narayanan, Ramesh, Weigel, Nancy L. +1 more·2005·Molecular and Cellular Biology

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 RARalpha and inducing degradation through the ubiquitin-proteasomal pathway. Analysis of RARalpha mutants and phosphopeptide mapping revealed that RARalpha residues Thr181, Ser445, and Ser461 are phosphorylated by JNK. Mutation of these residues to alanines prevented efficient ubiquitination of RARalpha and increased the stability of the protein. We investigated the importance of RARalpha 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 RARalpha levels and were resistant to treatment with an RAR ligand. JNK inhibition in a human lung cancer cell line enhanced RARalpha 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.

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Crossref · 10.1128/mcb.25.3.1054-1069.2005

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  • In these cancers and others, the RA-induced activation of the MAPK pathway is abrogated, and RARα and RXRα are aberrantly phosphorylated.

    “Most interestingly, in these cancers and others, the RA-induced activation of the MAPK pathway is abrogated ( 115 ), and RAR ␣ and RXR ␣ are aberrantly phosphorylated ( 166-168 ).”

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Authors
Srinivas, H., Juroske, D. M., Kalyankrishna, S., Cody, D. D., Price, R. E., Xu, X.-C., Narayanan, R., Weigel, N. L., & Kurie, J. M.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • Departments of Thoracic/Head and Neck Medical Oncology
  • Imaging Physics
  • Baylor College of Medicine (US)
Venue
Molecular and Cellular Biology
Published
2005-02-01
Volume
25
Issue
3
Pages
1054-1069
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
OpenAlex
W2141745343
Cited by
68
References
86
Citations by year
2026: 2 · 2025: 1 · 2023: 1 · 2021: 2 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 2 · 2015: 6 · 2014: 5 · 2013: 5 · 2012: 1
FWCI
3.15
Type
journal article
Language
en
Open access
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (R01CA080686, U01-CA84306, R01 CA 80686, U01CA084306)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
c-Jun N-terminal kinase, retinoic acid receptor alpha, retinoid signaling, lung cancer, protein phosphorylation, ubiquitin-proteasome degradation, retinoid resistance, K-ras oncogene, protein stability, JNK inhibition
MeSH terms
Retinoic Acid Receptor alpha, Animals, Chlorocebus aethiops, HeLa Cells, Humans, Lung Neoplasms, Mice, Transgenic, Mutation, Phosphorylation, Genes, ras, Tretinoin, Tumor Cells, Cultured, Ultraviolet Rays, Signal Transduction, 3T3 Cells, Receptors, Retinoic Acid, COS Cells, Ubiquitin, Proteasome Endopeptidase Complex, JNK Mitogen-Activated Protein Kinases, Mice

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