title: Identification and characterization of the human retinoid X receptor alpha gene promoter.
abstract: Retinoid X receptors (RXRs) comprise a family of nuclear retinoid activated transcription factors that are members of the steroid hormone receptor superfamily. RXRs are obligate heterodimerization partners with several other hormone receptor family members, making them critical mediators of a wide range of signaling pathways. Retinoids have been used successfully for the prevention of a number of epithelial cancers, including skin squamous cell carcinoma (SCC). The reduced expression levels of retinoid receptors including RXRalpha, the predominant RXR expressed in skin, is associated with malignancy in skin SCC. In order to study the regulation of RXRalpha in skin SCC carcinogenesis we have previously mapped the majority of the human RXRalpha gene. In the present study we have identified its first exon and promoter region. Exon 1, which contains the translation start site, is located in a highly G+C rich region of the genome at least 58 kb centromeric from exon 2. The promoter region itself is unusually G+C rich (75% G+C in 1200 bp of upstream sequence), has 17 putative SP1 transcription factor binding sites and no TATA or CAAT boxes. Transient transfection experiments with RXRalpha promoter-luciferase reporter constructs in SRB12-p9 skin SCC cells, as well as with PC3 prostate carcinoma cells, revealed that RXRalpha transcription is relatively weak compared to the positive control thymidine kinase (TK) promoter and is stimulated by treatment with all-trans retinoic acid (ATRA), the biologically active form of vitamin A. These results indicate that the RXRalpha gene is transcribed at stable levels, similar to most housekeeping genes, and its transcription is regulated by ATRA. In addition, the 5' untranslated region of RXRalpha is highly G+C rich, resulting in a potentially stable folding pattern, that would place RXRalpha amongst a group of genes that are subject to regulation at the translational level.
authors.affiliation: Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Guojun
authors.initials: G
authors.lastname: Li
authors.forename: Weihong
authors.initials: W
authors.lastname: Yin
authors.forename: Robert
authors.initials: R
authors.lastname: Chamberlain
authors.forename: David
authors.initials: D
authors.lastname: Hewett-Emmett
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: Roberts
authors.forename: Xiulan
authors.initials: X
authors.lastname: Yang
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.forename: John L
authors.initials: JL
authors.lastname: Clifford
mesh_terms: D000818:Animals; D001482:Base Composition / Q000235:genetics; D001483:Base Sequence; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D051379:Mice; D009690:Nucleic Acid Conformation; D020161:Physical Chromosome Mapping; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D047490:Retinoid X Receptor alpha / Q000235:genetics*; D017422:Sequence Analysis, DNA; D024363:Transcription Initiation Site; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D047490:Retinoid X Receptor alpha; D014212:Tretinoin