S-Space College of Medicine/School of Medicine (의과대학/대학원) Molecular and Genomic Medicine (분자유전체의학전공) Journal Papers (저널논문_분자유전체의학전공)
HIF-1alpha controls keratinocyte proliferation by up-regulating p21(WAF1/Cip1)
- Cho, Young-Suk; Bae, Jae-Moon; Chun, Yang-Sook; Chung, Jin-Ho; Jeon, Yoon-Kyung; Kim, In-San; Kim, Myung-Suk; Park, Jong-Wan
- Issue Date
- Elsevier/North Holland
- Biochim Biophys Acta. 2008 Feb;1783(2):323-33. Epub 2007 Dec 8.
- Animals; Cell Count; Cell Cycle; Cell Proliferation; Cells, Cultured; Cyclin-Dependent Kinase Inhibitor p21/*genetics; Epidermis/cytology/metabolism; Extracellular Signal-Regulated MAP Kinases/metabolism; Homeostasis; Humans; Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism; Keratinocytes/*cytology/enzymology; Mitochondria/metabolism; Mitogen-Activated Protein Kinase Kinases/metabolism; Rats; Reactive Oxygen Species/metabolism; Thermodynamics; Up-Regulation/*genetics
- 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.
- 0006-3002 (Print)
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