Cited by 57Retinoids in leukemia and cellular processesPeroxisome Proliferator-Activated ReceptorsNuclear Receptors and Signaling

Akt phosphorylates and suppresses the transactivation of retinoic acid receptor α

Open access
Srinivas, Harish, Xia, Dianren, Moore, Nicole L., Uray, Ivan P., Kim, Heetae, Ma, Long, Weigel, Nancy L., Brown, Powel H. +1 more·2006·Biochemical Journal

Abstract

The transactivation of nuclear receptors is regulated by both ligand binding and phosphorylation. We previously showed that RARα (retinoic acid receptor α) phosphorylation by c-Jun N-terminal kinase contributes to retinoid resistance in a subset of NSCLC cells (non-small cell lung cancer cells), but the aetiology of this resistance in the remainder has not been fully elucidated [Srinivas, Juroske, Kalyankrishna, Cody, Price, Xu, Narayanan, Weigel and Kurie (2005) Mol. Cell. Biol. 25, 1054–1069]. In the present study, we report that Akt, which is constitutively activated in NSCLC cells, phosphorylates RARα and inhibits its transactivation. Biochemical and functional analyses showed that Akt interacts with RARα and phosphorylates the Ser96 residue of its DNA-binding domain. Mutation of Ser96 to alanine abrogated the suppressive effect of Akt. Overexpression of a dominant-negative form of Akt in an NSCLC cell line decreased RAR phosphorylation, increased RAR transactivation and enhanced the growth-inhibitory effects of an RAR ligand. The findings presented here show that Akt inhibits RAR transactivation and contributes to retinoid resistance in a subset of NSCLC cells.

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Crossref · 10.1042/bj20051794

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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., Xia, D., Moore, N. L., Uray, I. P., Kim, H., Ma, L., Weigel, N. L., Brown, P. H., & Kurie, J. M.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • Baylor College of Medicine (US)
  • Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, U.S.A.
Corresponding author
  • Srinivas, Harish
  • Xia, Dianren
Venue
Biochemical Journal
Published
2006-04-11
Volume
395
Issue
3
Pages
653-662
ISSN
  • 0264-6021 (ISSN-L)
  • 1470-8728
OpenAlex
W2001536896
Cited by
49
References
53
Citations by year
2025: 1 · 2024: 3 · 2023: 3 · 2021: 3 · 2020: 2 · 2019: 5 · 2017: 2 · 2016: 3 · 2015: 2 · 2014: 5 · 2013: 3 · 2012: 2
FWCI
1.36
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Biochemical Journal (publishedVersion)
  • PubMed (publishedVersion)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
  • University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
Funders
National Cancer Institute (R01CA080686)
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 › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
Akt, retinoic acid receptor alpha, protein phosphorylation, retinoid resistance, non-small cell lung cancer, DNA-binding domain, nuclear receptor regulation, dominant-negative Akt
MeSH terms
Retinoic Acid Receptor alpha, Animals, Cell Line, Chlorocebus aethiops, DNA, DNA-Binding Proteins, Humans, Ligands, Mutation, Phosphorylation, Phosphoserine, Protein Binding, Retinoids, Substrate Specificity, Transcriptional Activation, Down-Regulation, Receptors, Retinoic Acid, Proto-Oncogene Proteins c-akt

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