Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1783, Issue 2, Pages 323-333Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2007.11.017
Keywords
hypoxia-inducible factor 1 alpha; p21; keratinocyte; cell density; growth arrest
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Funding
- National Research Foundation of Korea [R01-2006-000-10977-0] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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 1 alpha (HIF-1 alpha) 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-1 alpha 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-1 alpha expression. HIF-1 alpha siRNAs inhibited p21 expression and released the G1 arrest. In vivo, moreover, the intradermal injection of HIF-1 alpha 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-1 alpha stabilization in keratinocytes. These results imply that HIF-1 alpha functions as an up-stream player in the p21-mediated growth arrest of keratinocytes. (C) 2007 Elsevier B.V. All rights reserved.
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