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Loss of CAK phosphorylation of RAR{alpha} mediates transcriptional control of retinoid-induced cancer cell differentiation.

Abstract
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 alpha (RARalpha) is a transcription factor activated by RA, and its serine 77 (RARalphaS77) 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 RARalpha or mutation of RARalphaS77 to alanine (RARalphaS77A) coordinates CAK-dependent G(1) arrest with cancer cell differentiation by transactivating RA-target genes. Both hypophosphorylated RARalpha and RARalphaS77A reduce binding to retinoic acid-responsive elements (RARE) in the promoters of RA-target genes while stimulating gene transcription. The enhanced transactivation and reduced RARalpha-chromatin interaction are accompanied by RARalpha dissociation from the transcriptional repressor N-CoR and are association with the coactivator NCoA-3. Such effects of decreased CAK phosphorylation of RARalphaS77 on mediating RA-dependent transcriptional control of cancer cell differentiation are examined correspondingly in both RA-resistant myeloid leukemia and embryonic teratocarcinoma stem RARalpha(-/-) cells. These studies demonstrate, for the first time, that RA couples G(1) arrest to transcriptional control of cancer cell differentiation by suppressing CAK phosphorylation of RARalpha to release transcriptional repression.-Wang, A., Alimova, I. N., Luo, P. Jong, A., Triche, T. J., Wu, L. Loss of CAK phosphorylation of RARalpha mediates transcriptional control of retinoid-induced cancer cell differentiation.
AuthorsAnxun Wang, Irina N Alimova, Peihua Luo, Ambrose Jong, Timothy J Triche, Lingtao Wu
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 24 Issue 3 Pg. 833-43 (Mar 2010) ISSN: 1530-6860 [Electronic] United States
PMID19917671 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • RARA protein, human
  • Rara protein, mouse
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Tretinoin
  • Cyclin-Dependent Kinases
  • Cyclin-Dependent Kinase-Activating Kinase
Topics
  • Animals
  • Blotting, Western
  • Cell Cycle (genetics, physiology)
  • Cell Differentiation (drug effects, genetics)
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Cyclin-Dependent Kinases (metabolism)
  • Electrophoretic Mobility Shift Assay
  • Humans
  • Mice
  • Phosphorylation (physiology)
  • Promoter Regions, Genetic (genetics)
  • Protein Binding (drug effects)
  • Receptors, Retinoic Acid (metabolism)
  • Retinoic Acid Receptor alpha
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic (drug effects, genetics)
  • Tretinoin (pharmacology)
  • Cyclin-Dependent Kinase-Activating Kinase

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