The retinal dehydrogenase/reductase retSDR1/DHRS3 gene is activated by p53 and p63 but not by mutants derived from tumors or EEC/ADULT malformation syndromes.
Retinol and its metabolites have important roles in many processes including embryonic development, cellular differentiation, apoptosis and maintenance of epithelia. Retinal short-chain dehydrogenase/reductase retSDR1, also known as dehydrogenase/reductase member 3 (DHRS3), is involved in maintaining the cellular supply of retinol metabolites. We observe that retSDR1 expression is activated by members of the p53 family. Particularly p53 and TAp63γ regulate transcription through two separate response elements in the retSDR1 promoter. Both proteins bind the promoter in vitro and in vivo. Induction of DNA damage leads to recruitment of p53 and p63 to the retSDR1 promoter. A tumor-derived p53 mutant is unable to activate retSDR1 transcription. As mutants of p63 in humans exhibit phenotypes that cause several autosomal dominantly inherited syndromes leading to developmental malformations, we tested the transcriptional response of TAp63γ mutants derived from the EEC, SHFM and ADULT syndromes. EEC syndrome-specific mutations of TAp63γ fail to transactivate retSDR1 and an ADULT syndrome-derived mutant stimulates retSDR1 transcription significantly less than the wild-type variant of p63. Taken together, the results suggest a potential role of the p53/p63-mediated retSDR1 activation in tumor suppression as well as in developmental processes.
Kirschner
Ralf D
RD
Department of Obstetrics and Gynecology, University of Leipzig, Leipzig, Germany.
Rother
Karen
K
Müller
Gerd A
GA
Engeland
Kurt
K
D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D004249:DNA Damage; D004476:Ectodermal Dysplasia / Q000235:genetics*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C115051:TP63 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000429:Alcohol Oxidoreductases; C084155:alcohol dehydrogenase (NAD(P)+)