Loss of CAK phosphorylation of RARa mediates transcriptional control of retinoid‐induced cancer cell differentiation

Although the role of the classic retinoic acid (RA)‐induced genomic pathway in cancer cell differentiation is well recognized, the underlying mechanisms remain to be dissected. Retinoic acid receptor a (RARa) is a transcription factor activated by RA, and its serine 77 (RARaS77) is the main residue...

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Published in:	The FASEB journal Vol. 24; no. 3; pp. 833 - 843
Main Authors:	Wang, Anxun, Alimova, Irina N., Luo, Peihua, Jgon, Ambrose, Triche, Timothy J., Wu, Lingtao
Format:	Journal Article
Language:	English
Published:	Federation of American Societies for Experimental Biology 01-03-2010
Subjects:	cell cycle G1 exit decreased CAK activity by RA gene transcription transcriptional repression
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Summary:	Although the role of the classic retinoic acid (RA)‐induced genomic pathway in cancer cell differentiation is well recognized, the underlying mechanisms remain to be dissected. Retinoic acid receptor a (RARa) is a transcription factor activated by RA, and its serine 77 (RARaS77) is the main residue phosphorylated by the cyclin‐dependent kinase (CDK)‐activating kinase (CAK) complex. We report here that in both human myeloid leukemia and mouse embryonic teratocarcinoma stem cells, either RA‐suppressed CAK phosphorylation of RARa or mutation of RARaS77 to alanine (RARaS77A) coordinates CAK‐dependent G1 arrest with cancer cell differentiation by transactivating RA‐target genes. Both hypophosphorylated RARa and RARaS77A reduce binding to retinoic acid‐responsive elements (RARE) in the promoters of RA‐target genes while stimulating gene transcription. The enhanced transactivation and reduced RARa‐chromatin interaction are accompanied by RARa dissociation from the transcriptional repressor N‐CoR and are association with the coactivator NCoA‐3. Such effects of decreased CAK phosphorylation of RARaS77 on mediating RA‐dependent transcriptional control of cancer cell differentiation are examined correspondingly in both RA‐resistant myeloid leukemia and embryonic teratocarcinoma stem RARa‐/‐ cells. These studies demonstrate, for the first time, that RA couples G1 arrest to transcriptional control of cancer cell differentiation by suppressing CAK phosphorylation of RARa to release transcriptional repression.—Wang, A, Alimova, I. N., Luo, P. Jong, A, Triche, T. J., Wu, L. Loss of CAK phosphorylation of RARa mediates transcriptional control of retinoid‐induced cancer cell differentiation. FASEB J. 24, 833–843 (2010). www.fasebj.org
Bibliography:	These authors contributed equally to this work.
ISSN:	0892-6638 1530-6860
DOI:	10.1096/fj.09-142976