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HIF-1alpha controls keratinocyte proliferation by up-regulating p21(WAF1/Cip1)

Cited 37 time in Web of Science Cited 37 time in Scopus
Authors
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
2008-01-02
Publisher
Elsevier/North Holland
Citation
Biochim Biophys Acta. 2008 Feb;1783(2):323-33. Epub 2007 Dec 8.
Keywords
AnimalsCell CountCell CycleCell ProliferationCells, CulturedCyclin-Dependent Kinase Inhibitor p21/*geneticsEpidermis/cytology/metabolismExtracellular Signal-Regulated MAP Kinases/metabolismHomeostasisHumansHypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolismKeratinocytes/*cytology/enzymologyMitochondria/metabolismMitogen-Activated Protein Kinase Kinases/metabolismRatsReactive Oxygen Species/metabolismThermodynamicsUp-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
DOI
https://doi.org/10.1016/j.bbamcr.2007.11.017
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College of Medicine/School of Medicine (의과대학/대학원)Molecular and Genomic Medicine (분자유전체의학전공)Journal Papers (저널논문_분자유전체의학전공)
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