Retinoic acid receptors and GATA transcription factors activate the transcription of the human lecithin:retinol acyltransferase gene.
Lecithin:retinol acyltransferase (LRAT) catalyzes the esterification of retinol (vitamin A). Retinyl esters and LRAT protein levels are reduced in many types of cancer cells. We present data that both the LRAT and retinoic acid receptor beta(2) (RARbeta(2)) mRNA levels in the human prostate cancer cell line PC-3 are lower than those in cultured normal human prostate epithelial cells (PrEC). The activity of the human LRAT promoter (2.0 kb) driving a luciferase reporter gene in PC-3 cells is less than 40% of that in PrEC cells. Retinoic acid (RA) treatment increased this LRAT promoter-luciferase activity in PrEC cells, but not in PC-3 cells. Deletion of various regions of the human LRAT promoter demonstrated that a 172-bp proximal promoter region is essential for LRAT transcription and confers RA responsiveness in PrEC cells. This 172-bp region, contained within the 186 bp pLRAT/luciferase construct, has five putative GATA binding sites. Cotransfection of RARbeta(2) or RARgamma and the transcription factor GATA-4 increased LRAT (pLRAT186) promoter activity in both PrEC and PC-3 cells. In addition, we found that both retinoic acid and retinol induced transcripts for the STRA6 gene, which encodes a membrane receptor involved in retinol (vitamin A) uptake, in PrEC cells but not in PC-3 cells. In summary, our data show that the transcriptional regulation of the human LRAT gene is aberrant in human prostate cancer cells and that GATA transcription factors are involved in the transcriptional activation of LRAT in PrEC cells.
Cai
Kun
K
Department of Pharmacology, Weill Cornell Medical College, New York, NY 10021, USA.
Gudas
Lorraine J
LJ
D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000166:cytology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015533:Transcriptional Activation; D014162:Transfection; D014801:Vitamin A / Q000378:metabolism; D000097768:Retinoic Acid Receptor gamma
D000217:Acyltransferases; D050991:GATA4 Transcription Factor; D008565:Membrane Proteins; D018168:Receptors, Retinoic Acid; D014801:Vitamin A; D000097768:Retinoic Acid Receptor gamma; C533416:RARB2 protein, human; C519685:STRA6 protein, human; C056942:lecithin-retinol acyltransferase