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: Yuko Imamura, Shuhei Tomita, Masaki Imanishi, Yoshitaka Kihira, Yasumasa Ikeda, Keisuke Ishizawa, Koichiro Tsuchiya, Toshiaki Tamaki
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 28 Issue 6 Pg. 2517-24 (Jun 2014) ISSN: 1530-6860 [Electronic] United States
• PMID: 24599965 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © FASEB.

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Cyclin-Dependent Kinase Inhibitor p21
• Hypoxia-Inducible Factor 1, alpha Subunit
• Aryl Hydrocarbon Receptor Nuclear Translocator
• Cyclin-Dependent Kinase Inhibitor p27
• endothelial PAS domain-containing protein 1

Topics

• Animals
• Aryl Hydrocarbon Receptor Nuclear Translocator (metabolism)
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Cell Differentiation (drug effects)
• Cells, Cultured
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Hair (growth & development)
• Hair Follicle (cytology, metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Keratinocytes
• Mice
• Mice, Knockout