TNFa induces HIF-1a expression through activation of IKKB

ASIA unversity > 醫學暨健康學院 > 生物科技學系 > 期刊論文 > Item 310904400/16138

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题名:	TNFa induces HIF-1a expression through activation of IKKB
作者:	Hsu-Ping Kuo;Dung-Fang Lee;Weiya Xia;Yongkun Wei;Mien-Chie Hung
贡献者:	生物科技學系
日期:	2009
上传时间:	2012-11-23 09:09:03 (UTC+0)
摘要:	The transcription factor hypoxia-inducible factor 1 alpha (HIF-1 alpha) is regulated by oxygen availability as well as various inflammatory mediators, including tumor necrosis factor alpha (TNF alpha). Early work suggested that the phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways are involved in TNF alpha-mediated HIF-1 alpha accumulation and activation under normoxic conditions. Here, we provide evidence showing that I kappa B kinase beta (IKK beta) is required for HIF-1 alpha regulation by TNF alpha. We found that TNF alpha enhances HIF-1 alpha protein expression in various breast cancer cell lines under either normoxic or hypoxia-mimicking conditions, but has little effect on the HIF-1 alpha mRNA level. Increased HIF-1 alpha expression was found in IKK beta stable clones and transient transfectants, and depletion of IKK beta consistently reduced the amount of HIF-1 alpha protein. Treatment of cells with the IKK beta inhibitor Bay 11-7082 reduced the TNF alpha-induced HIF-1 alpha expression, suggesting that IKK beta is required in this signaling pathway. Decreased expression of vascular endothelial growth factor (VEGF), a direct target of HIF-1 alpha, was shown in IKK beta-knockout mouse embryonic fibroblast cells. We further demonstrated a positive correlation between IKK beta and VEGF expression in primary human breast cancer specimens. Our findings indicate that TNF alpha-induced HIF-1 alpha accumulation is IKK beta dependent, and may enable further understanding of the HIF-1 alpha regulation by inflammatory signals. (C) 2009 Elsevier Inc. All rights reserved.
關聯:	BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,389(4),640-644.
显示于类别:	[生物科技學系] 期刊論文

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