HIF-2α/ARNT complex regulates hair development via induction of p21Waf1/Cip1 and p27Kip1.
HIF-2α/ARNT complex regulates hair development via induction of p21Waf1/Cip1 and p27Kip1.
复制标题
HIF-2α/ARNT 复合物通过诱导 p21Waf1/Cip1 和 p27Kip1 调节毛发发育。
作者：
Imamura Y;Tomita S;Imanishi M;Kihira Y;Ikeda Y;Ishizawa K;Tsuchiya K;Tamaki T.
缺氧诱导因子HIF-1α或HIF-2α与芳香烃受体核转位蛋白（ARNT）形成异二聚体复合物。HIF-1α/ARNT和HIF-2α/ARNT复合物激活缺氧诱导基因，这些基因在血管生成、无氧代谢和其他响应氧剥夺的过程中发挥关键作用。已知HIF-2α通过激活POU结构域转录因子Oct 4来调节干细胞的功能和/或分化;然而，确切的潜在机制尚不清楚。本研究使用条件性基因敲除小鼠检测了HIF-2α/ARNT在毛发发育中的作用，其中Arnt在角质形成细胞中特异性缺失。在野生型小鼠中，HIF-2α和ARNT在毛基质上方的前皮质中高度表达，这是一个含有分化干细胞的区域。对这些小鼠毛发大小和类型的分析表明，ARNT的缺失减少了锯齿状毛发的产生，对应于HIF-2α表达的减少和哺乳动物细胞周期蛋白依赖性激酶抑制剂p21 Waf 1/Cip 1和p27 Kip 1的诱导。结果表明，HIF-2α/ARNT复合物通过诱导p21 Waf 1/Cip 1和可能的p27 Kip 1来调节毛囊分化，因为在ARNT敲除小鼠中p27 Kip 1表达没有改变。这些发现提供了对毛发生长障碍潜在机制的深入了解，并可用于未来研究毛囊对化疗和电离辐射等损伤的反应。Imamura，Y.，Tomita，S.，Imanishi，M.，Kihira，Y.，Ikeda，Y.，Ishizawa，K.，Tsuchiya，K.，Tamaki，T. HIF-2α/ARNT complex regulates hair development via induction of p21Waf1/Cip1 and p27Kip1. FASEB J. 28，2517-2524（2014）. www.fasebj.org
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 O2deprivation. 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 whichArntwas 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 p21Waf1/Cip1andp27Kip1The results suggest that the HIF‐2α/ARNT complex regulates hair follicle differentiationviainduction of p21Waf1/Cip1and possibly p27Kip1, as p27Kip1expression 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.—Imamura, Y., Tomita, S., Imanishi, M., Kihira, Y., Ikeda, Y., Ishizawa, K., Tsuchiya, K., Tamaki, T. HIF‐2α/ARNT complex regulates hair developmentviainduction of p21Waf1/Cip1and p27Kip1.FASEB J. 28, 2517–2524 (2014). www.fasebj.org