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HIF-1alpha controls keratinocyte proliferation by up-regulating p21(WAF1/Cip1)
Cited 44 time in
Web of Science
Cited 45 time in Scopus
- Authors
- Issue Date
- 2008-01-02
- Publisher
- Elsevier/North Holland
- Citation
- Biochim Biophys Acta. 2008 Feb;1783(2):323-33. Epub 2007 Dec 8.
- Keywords
- 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
- Abstract
- 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.
- ISSN
- 0006-3002 (Print)
- Language
- English
- URI
- http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T20-4R9GGN2-2&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=af4a81de8cb439ab2d137359da8c5277
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18166158
https://hdl.handle.net/10371/46597
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