Retinoic acid receptor-related orphan receptor RORα regulates differentiation and survival of keratinocytes during hypoxia.
Low O2pressures present in the microenvironment of epidermis control keratinocyte differentiation and epidermal barrier function through hypoxia inducible factors (HIFs) dependent gene expression. This study focuses on investigating relations of the retinoic acid receptor-related orphan receptor alpha (RORα) to HIF-1α in keratinocytes under hypoxic conditions. The expression level of RORα is significantly elevated under hypoxia in both human and murine keratinocytes. Gene silencing of RORA attenuates hypoxia-stimulated expression of genes related to late differentiation and epidermal barrier function, and leads to an enhanced apoptotic response. While the hypoxic induction of RORα is dependent on HIF-1α, RORα is in turn critical for nuclear accumulation of HIF-1α and activation of HIF transcriptional activity. These results collectively suggest that RORα functions as an important mediator of HIF-1α activities in regulating keratinocyte differentiation/survival and epidermal barrier function during the oxygen sensing stage.
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, P. R. China.
Hongyu
H
Li
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, P. R. China.
Longjian
L
Zhou
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, P. R. China.|Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts.|Division of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin, Madison, Wisconsin.
Jun
http://orcid.org/0000-0002-9243-3350
J
Dai
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D015687:Cell Hypoxia; D002460:Cell Line; D002470:Cell Survival; D060833:Cellular Microenvironment; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human; C539739:Rora protein, mouse
HIF-1α; RORα; apoptosis; differentiation; hypoxia; keratinocytes