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retSDR1, a Short-Chain Retinol Dehydrogenase/Reductase, Is Retinoic Acid-inducible and Frequently Deleted in Human Neuroblastoma Cell Lines¹

Department of Experimental Medicine and Pathology, University La Sapienza, 00161 Rome, Italy^,3 [L. F., I. S., A. G., G. G.]; Department of Experimental Medicine, University of L’Aquila, 67100 L’Aquila, Italy [F. C.]; Neuromed Institute, 86077 Pozzilli, Italy [C. R., L. F.]; Pasteur Institute Cenci-Bolognetti Foundation, 00161 Rome, Italy [I. S.]; Institute of Cell Biology, Consiglio Nazionale delle Ricerche (CNR), 00016 Monterotondo, Italy [B. C.]; Department of Pharmacology, Weill Medical College of Cornell University, New York, New York, 10021 [X. G., L. J. G.]; and Cellular and Molecular Biology Section, National Cancer Institute, NIH, Bethesda, Maryland^,3 20892 [J. C., C. J. T.]

Vitamin A is required for a number of developmental processes and for the homeostatic maintenance of several adult differentiated tissues and organs. In human neuroblastoma (NB) cells as well as some other tumor types, pharmacological doses of retinoids are able to control growth and induce differentiation in vitro and in vivo. In a search for new genes that are regulated by retinoids and that contribute to the biological effects retinoids have on NB cells, we have isolated five differentially expressed transcripts. Here we report on the characterization of one of them (DD83.1) in NB cell lines. DD83.1 is identical to the human retSDR1, a short chain dehydrogenase/reductase that is thought to regenerate retinol from retinal in the visual cycle. Its expression is strongly, but differently, regulated by retinoids in NB cell lines, and it is widely expressed in human tissues, which suggests that it is involved in a more general retinol metabolic pathway. Both the retinoic acid-dependent and the exogenous expression of retSDR1 in SK-N-AS cells induce the accumulation of retinyl esters, which indicates that it is involved in generating storage forms of retinol in tissues exposed to physiological retinol concentrations. We also show that the human retSDR1 gene, which maps on chromosome 1p36.1, is contained in the DNA fragment deleted in many NB cell lines bearing MYCN amplification but is conserved in a cell line with a small 1p deletion and normal MYCN. Our observations suggest that retSDR1 is a novel regulator of vitamin A metabolism and that its frequent deletion in NB cells bearing MYCN amplification could compromise the sensitivity of those cells to retinol, thereby contributing to cancer development and progression.

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