title: HIF-2α/ARNT complex regulates hair development via induction of p21(Waf1/Cip1) and p27(Kip1).
abstract: The hypoxia-inducible factors HIF-1α or HIF-2α form heterodimeric complexes with the aryl hydrocarbon receptor nuclear translocator (ARNT). HIF-1α/ARNT and HIF-2α/ARNT complexes activate hypoxia-inducible genes that play critical roles in angiogenesis, anaerobic metabolism, and other processes in response to O2 deprivation. HIF-2α is known to regulate the function and/or differentiation of stem cells by activating the POU domain transcription factor Oct4; however, the precise underlying mechanism is unknown. This study examined the role of HIF-2α/ARNT in hair development using conditional-knockout mice, in which Arnt was specifically deleted in keratinocytes. In wild-type mice, HIF-2α and ARNT were highly expressed in the precortex above the hair matrix, an area containing differentiating stem cells. An analysis of hair size and type in these mice showed that loss of ARNT decreased the production of zigzag hairs, corresponding to reduced expression of HIF-2α and induction of the mammalian cyclin-dependent kinase inhibitors p21(Waf1/Cip1) and p27 (Kip1). The results suggest that the HIF-2α/ARNT complex regulates hair follicle differentiation via induction of p21(Waf1/Cip1) and possibly p27(Kip1), as p27(Kip1) expression was not altered in ARNT knockout mice. The findings provide insight into a possible mechanism underlying hair growth disorders and can be useful for future studies on hair follicle response to insults, such as chemotherapy and ionizing radiation.
authors.affiliation: Department of Pharmacology and Department of Molecular Biotechnology, Graduate School of Advanced Sciences, Hiroshima University, Higashihiroshima City, Japan; and yukoima@hiroshima-u.ac.jp.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Imamura
authors.affiliation: Division of Molecular Pharmacology, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Tomita
authors.affiliation: Department of Pharmacology and.
authors.forename: Masaki
authors.initials: M
authors.lastname: Imanishi
authors.affiliation: Department of Pharmacology and.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Kihira
authors.affiliation: Department of Pharmacology and.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ikeda
authors.affiliation: Department of Medical Pharmacology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan;
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ishizawa
authors.affiliation: Department of Medical Pharmacology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan;
authors.forename: Koichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Department of Pharmacology and.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tamaki
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D006197:Hair / Q000254:growth & development*; D018859:Hair Follicle / Q000166:cytology / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D015603:Keratinocytes; D051379:Mice; D018345:Mice, Knockout; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: cell differentiation; cyclin-dependent kinase inhibitor; hypoxia-inducible factor