HIF-1alpha controls keratinocyte proliferation by up-regulating p21(WAF1/Cip1).
The cyclin-dependent kinase inhibitor p21(WAF1/Cip1) plays a central role in a spatial and temporal balance of epidermal keratinocyte proliferation and growth arrest. However, what controls p21 expression in keratinocytes remains uncertain. Hypoxia-inducible factor 1alpha (HIF-1alpha) does not only express a variety of genes essential for hypoxic adaptation, but also up-regulates p21 so as to slow down cell cycle under hypoxic conditions. In the present study, we examined the role of HIF-1alpha in p21-mediated growth arrest of keratinocyte. Keratinocyte proliferation was arrested in the G1 phase at a high cell density. p21 was also up-regulated in a cell density-dependent manner and was found to be highly expressed in epidermal keratinocytes of normal human skins. In addition, in the same specimens and cells, we noted robust HIF-1alpha expression. HIF-1alpha siRNAs inhibited p21 expression and released the G1 arrest. In vivo, moreover, the intradermal injection of HIF-1alpha siRNA attenuated p21 expression in rat epidermis and induced skin hyperplasia. Mechanistically, we propose that the production of mitochondrial reactive oxygen species and the activation of the MEK/ERK pathway are involved in the HIF-1alpha stabilization in keratinocytes. These results imply that HIF-1alpha functions as an up-stream player in the p21-mediated growth arrest of keratinocytes.
Cho
Young-Suk
YS
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Bae
Jae-Moon
JM
Chun
Yang-Sook
YS
Chung
Jin-Ho
JH
Jeon
Yoon-Kyung
YK
Kim
In-San
IS
Kim
Myung-Suk
MS
Park
Jong-Wan
JW
D000818:Animals; D002452:Cell Count; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology* / Q000201:enzymology; D008928:Mitochondria / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013816:Thermodynamics; D015854:Up-Regulation / Q000235:genetics*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases