The A/B domain of truncated retinoic acid receptors can block differentiation and promote features of malignancy.
Recently, we discovered that stable introduction of a carboxyl-terminally truncated retinoic acid receptor gamma (tRAR gamma) into an epidermal keratinocyte line blocked the ability of these cells to differentiate, as judged by their failure to express late markers of squamous differentiation. We now demonstrate a correlation between the level of residual endogenous RAR activity of tRAR gamma-expressing keratinocyte lines and degree of terminal differentiation. Mutagenesis studies localize the effects to the A/B subdomain of the truncated receptor. Despite tRAR gamma's capacity to interfere with RAR-mediated transactivation of retinoic acid response elements (RAREs) in keratinocytes, the effects of the truncated receptor are independent of its ability to bind DNA and directly interact with endogenous RARs. tRAR alpha also inhibits RARE-mediated gene expression in keratinocytes, even though its full-length counterpart enhances RARE activity in these cells. Intriguingly, both tRAR gamma and RAR gamma suppress keratin promoter activity in epidermal cells, although for tRAR gamma, the effect is mediated through the A/B domain whereas for RAR gamma, the effects require DNA binding. Taken together, these findings suggest that the truncation allows for new and aberrant interactions with transcriptional proteins/cofactors that participate in governing RARE activity. This discovery may have relevance in tumorigenesis, where genetic lesions can result in mutant RARs or in loss of receptor expression.
Aneskievich
B J
BJ
Department of Molecular Genetics and Cell Biology, Howard Hughes Medical Institute, University of Chicago, IL 60637, USA.
Fuchs
E
E
D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D004247:DNA / Q000378:metabolism; D017931:DNA Primers; D000078404:Epidermal Cells; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D007633:Keratins / Q000096:biosynthesis / Q000235:genetics; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology; D000072482:Retinoic Acid Receptor alpha; D017384:Sequence Deletion; D000097768:Retinoic Acid Receptor gamma
D004247:DNA; D017931:DNA Primers; D007633:Keratins; D009838:Oligodeoxyribonucleotides; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D000072482:Retinoic Acid Receptor alpha; D000097768:Retinoic Acid Receptor gamma; C000607071:RARA protein, human