TNFalpha induces HIF-1alpha expression through activation of IKKbeta.
TNFalpha induces HIF-1alpha expression through activation of IKKbeta.
复制标题
DOI：
10.1016/j.bbrc.2009.09.042
复制
发表时间：
2009-11-27
影响因子：
3.1
通讯作者：
Hung, Mien-Chie
中科院分区：
文献类型：
--
作者：
Kuo, Hsu-Ping;Lee, Dung-Fang;Xia, Weiya;Wei, Yongkun;Hung, Mien-Chie
关键词：
转录因子缺氧诱导因子1α（HIF-1α）受氧可用性以及各种炎症介质（包括肿瘤坏死因子α（TNFα））的调节。早期的研究表明，磷脂酰肌醇-3-激酶（PI 3 K）和丝裂原活化蛋白激酶（MAPK）信号通路参与了TNFα介导的HIF-1α在常氧条件下的积累和激活。在此，我们提供的证据表明Iκ B激酶β（IKKβ）是TNFα调节HIF-1α所必需的。我们发现TNFα在常氧或模拟低氧条件下可增强各种乳腺癌细胞系中HIF-1α蛋白的表达，但对HIF-1α mRNA水平的影响不大。在IKKβ稳定克隆和瞬时转染子中发现HIF-1α表达增加，并且IKKβ的消耗持续降低HIF-1α蛋白的量。用IKKβ抑制剂Bay 11-7082处理细胞可降低TNFα诱导的HIF-1α表达，表明IKKβ在该信号通路中是必需的。在IKKβ基因敲除小鼠胚胎成纤维细胞中，HIF-1α的直接靶点血管内皮生长因子（VEGF）表达降低。我们进一步证实了IKKβ和VEGF在原发性乳腺癌标本中的表达呈正相关。我们的研究结果表明TNFα诱导的HIF-1α积聚是IKKβ依赖性的，这可能有助于进一步理解炎症信号对HIF-1α的调节。
The transcription factor hypoxia-inducible factor 1α (HIF-1α) is regulated by oxygen availability as well as various inflammatory mediators, including tumor necrosis factor α (TNFα). Early work suggested that the phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways are involved in TNFα-mediated HIF-1α accumulation and activation under normoxic conditions. Here, we provide evidence showing that IκBkinase β (IKKβ) is required for HIF-1α regulation by TNFα. We found that TNFα enhances HIF-1α protein expression in various breast cancer cell lines under either normoxic or hypoxia-mimicking conditions, but has little effect on the HIF-1α mRNA level. Increased HIF-1α expression was found in IKKβ stable clones and transient transfectants, and depletion of IKKβ consistently reduced the amount of HIF-1α protein. Treatment of cells with the IKKβ inhibitor Bay 11-7082 reduced the TNFα-induced HIF-1α expression, suggesting that IKKβ is required in this signaling pathway. Decreased expression of vascular endothelial growth factor (VEGF), a direct target of HIF-1α, was shown in IKKβ-knockout mouse embryonic fibroblast cells. We further demonstrated a positive correlation between IKKβ and VEGF expression in primary human breast cancer specimens. Our findings indicate that TNFα-induced HIF-1α accumulation is IKKβ dependent, and may enable further understanding of the HIF-1α regulation by inflammatory signals.
登录
查看更多内容
影响因子：
64.5
作者：
Brunet, A;Bonni, A;Greenberg, ME
通讯作者：
Greenberg, ME
DOI：
10.1016/j.bbrc.2009.08.127
发表时间：
2009-11-06
影响因子：
3.1
作者：
Kuo, Hsu-Ping;Lee, Dung-Fang;Xia, Weiya;Lai, Chien-Chen;Li, Long-Yuan;Hung, Mien-Chie
通讯作者：
Hung, Mien-Chie
影响因子：
21.3
作者：
Yang, Jer-Yen;Zong, Cong S.;Hung, Mien-Chie
通讯作者：
Hung, Mien-Chie
影响因子：
4.8
作者：
Sang, NL;Stiehl, DP;Caro, J
通讯作者：
Caro, J
影响因子：
4.3
作者：
Lee, Dung-Fang;Hung, Mien-Chie
通讯作者：
Hung, Mien-Chie