title: 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.
authors.affiliation: Department of Pathology, MS# 103, Childrens Hospital Los Angeles, University of Southern California Keck School of Medicine, 4650 Sunset Blvd, Los Angeles, CA 90027, USA.
authors.forename: Anxun
authors.initials: A
authors.lastname: Wang
authors.forename: Irina N
authors.initials: IN
authors.lastname: Alimova
authors.forename: Peihua
authors.initials: P
authors.lastname: Luo
authors.forename: Ambrose
authors.initials: A
authors.lastname: Jong
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Triche
authors.forename: Lingtao
authors.initials: L
authors.lastname: Wu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D051379:Mice; D010766:Phosphorylation / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase