Deletion of RAR carboxyl terminus reveals promoter- and receptor-specific AF-1 effects.
Retinoic acid receptors (RARs) are transcription factors with both amino-terminal ligand-independent and carboxyl-terminal ligand-dependent activation functions (AF-1 and AF-2, respectively). RAR-dependent gene activation in keratinocytes was investigated via expression of varied RARalpha and RARgamma carboxyl terminal truncation mutants lacking the AF-2 domain. Overexpression of the AF-1 domain of RARalpha or RARgamma was sufficient to decrease transcriptional activation of retinoid-dependent genes in keratinocytes. Conversely, expression of the same constructs was associated with an increase in expression of endogenous and synthetic reporter genes otherwise negatively regulated by RARs. These effects on transcription driven by some but not all retinoid-sensitive promoters tested could be alleviated by mutation of a serine phosphorylation site in the A/B domain. These results further support the promoter-specificity previously attributed to the RAR AF-1 region and functionally define a particular amino acid residue likely to contribute to the regulation of RARs and other proteins in the transcription complex.
Aneskievich
B J
BJ
Department of Pharmaceutical Sciences, University of Connecticut, 372 Fairfield Road, U-92, Connecticut 06269, USA. aneskiev@uconnvm.uconn.edu
D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D017364:Collagenases / Q000096:biosynthesis; D015870:Gene Expression; D017930:Genes, Reporter; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D007633:Keratins / Q000096:biosynthesis; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D017384:Sequence Deletion; D012694:Serine / Q000737:chemistry; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D000097768:Retinoic Acid Receptor gamma
D017364:Collagenases; D007633:Keratins; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D012694:Serine; D018808:Transcription Factor AP-1; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C000607071:RARA protein, human; C082925:retinoic acid receptor beta