Loss of CAK phosphorylation of RARα mediates transcriptional control of retinoid-induced cancer cell differentiation

• Published in: The FASEB journal Vol. 24; no. 3; pp. 833 - 843
• Main Authors: Wang, Anxun, Alimova, Irina N, Luo, Peihua, Jong, Ambrose, Triche, Timothy J, Wu, Lingtao
• Format: Journal Article
• Language: English
• Published: The Federation of American Societies for Experimental Biology 01-03-2010
• Subjects: Research Communications
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.09-142976

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 α (RARα) is a transcription factor activated by RA, and its serine 77 (RARαS77) 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 RARα or mutation of RARαS77 to alanine (RARαS77A) coordinates CAK-dependent G₁ arrest with cancer cell differentiation by transactivating RA-target genes. Both hypophosphorylated RARα and RARαS77A reduce binding to retinoic acid-responsive elements (RARE) in the promoters of RA-target genes while stimulating gene transcription. The enhanced transactivation and reduced RARα-chromatin interaction are accompanied by RARα dissociation from the transcriptional repressor N-CoR and are association with the coactivator NCoA-3. Such effects of decreased CAK phosphorylation of RARαS77 on mediating RA-dependent transcriptional control of cancer cell differentiation are examined correspondingly in both RA-resistant myeloid leukemia and embryonic teratocarcinoma stem RARα⁻/⁻ 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 RARα to release transcriptional repression.--Wang, A., Alimova, I. N., Luo, P. Jong, A., Triche, T. J., Wu, L. Loss of CAK phosphorylation of RARα mediates transcriptional control of retinoid-induced cancer cell differentiation.