Abstract
The transcription factor p53 plays a critical role in maintaining homeostasis as it relates to cellular growth, proliferation, and metabolism. In an effort to identify novel p53 target genes, a microarray approach was utilized to identify DHRS3 (also known as retSDR1) as a robust candidate gene. DHRS3 is a highly conserved member of the short chain alcohol dehydrogenase/reductase superfamily with a reported role in lipid and retinoid metabolism. Here, we demonstrate that DHRS3 is an endoplasmic reticulum (ER) protein that is shuttled to the ER via an N-terminal endoplasmic reticulum targeting signal. One important function of the ER is synthesis of neutral lipids that are packaged into lipid droplets whose biogenesis occurs from ER-derived membranes. DHRS3 is enriched at focal points of lipid droplet budding where it also localizes to the phospholipid monolayer of ER-derived lipid droplets. p53 promotes lipid droplet accumulation in a manner consistent with DHRS3 enrichment in the ER. As a p53 target gene, the observations of Dhrs3 location and potential function provide novel insight into an unexpected role for p53 in lipid droplet dynamics with implications in cancer cell metabolism and obesity.
Highlights
AUGUST 12, 2011 VOLUME 286 NUMBER 32 ferase, an enzyme critical for creatine biosynthesis [5]
To preserve viability of the mice for further study, they were introduced with the switchable p53ERTAM (p53ER) allele [15] to facilitate modulation of p53 function. p53ER expresses a WT p53 protein fused at the C terminus to the hormone binding domain of the estrogen receptor and is transcriptionally regulated in the same manner as the WT allele
As a novel metabolic target gene of p53, DHRS3 is a well conserved protein that is actively targeted to the endoplasmic reticulum
Summary
AUGUST 12, 2011 VOLUME 286 NUMBER 32 ferase, an enzyme critical for creatine biosynthesis [5]. Ectopic expression of DHRS3 in neuroblastoma cells was reported to increase retinyl ester concentrations, supporting the role of DHRS3 as a retinal reductase in generating storage forms of retinol [10]. DHRS3 expression is enhanced in retinol storing tissues where it may be involved in promoting retinyl ester storage in nascent lipid droplets.
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