Induction of hypoxia-inducible factor 1 activity by muscarinic acetylcholine receptor signaling
Induction of hypoxia-inducible factor 1 activity by muscarinic acetylcholine receptor signaling
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DOI：
10.1074/jbc.m405164200
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发表时间：
2004-10-01
影响因子：
4.8
通讯作者：
Semenza, GL
中科院分区：
文献类型：
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作者：
Hirota, K;Fukuda, R;Semenza, GL
缺氧诱导因子-1（HIF-1）是细胞缺氧适应性反应的主要调节因子。HIF-1 α亚单位的水平在缺氧条件下增加。在非缺氧条件下，细胞暴露于生长因子、前列腺素和某些一氧化氮供体也诱导HIF-1 α表达。我们证明，毒蕈碱乙酰胆碱信号诱导HIF-1 α的表达和转录活性的受体亚型特异性的方式使用HEK 293细胞瞬时过表达M1-M4毒蕈碱乙酰胆碱受体。脉冲标记研究证实，毒蕈碱信号通路抑制HIF-1 α的羟基化和降解，并诱导HIF-1 α蛋白的合成。毒蕈碱信号诱导的HIF-1 α蛋白和HIF-1依赖的基因表达被阻断与磷脂酰肌醇3-激酶，MAP激酶激酶，或酪氨酸激酶信号通路的抑制剂处理细胞。显性负性形式的Ras和/或Rac-1通过毒蕈碱信号传导显著抑制HIF-1活化。通过M1-和M3-而不是M2-或M4-AchR的信号传导促进HIF-1 α的积累和转录激活。我们的结论是，毒蕈碱乙酰胆碱信号激活HIF-1的稳定和合成的HIF-1 α和诱导HIF-1 α的转录活性。
Hypoxia-inducible factor-1 (HIF-1) is a master regulator of cellular adaptive responses to hypoxia. Levels of the HIF-1alpha subunit increase under hypoxic conditions. Exposure of cells to growth factors, prostaglandin, and certain nitric oxide donors also induces HIF-1alpha expression under non-hypoxic conditions. We demonstrate that muscarinic acetylcholine signals induce HIF-1alpha expression and transcriptional activity in a receptor subtype-specific manner using HEK293 cells transiently overexpressing each of M1-M4 muscarinic acetylcholine receptors. The muscarinic signaling pathways inhibited HIF-1alpha hydroxylation and degradation and induced HIF-1alpha protein synthesis that was confirmed by pulse labeling studies. Muscarinic signal-induced HIF-1alpha protein and HIF-1-dependent gene expression were blocked by treating cells with inhibitors of phosphatidylinositol 3-kinase, MAP kinase kinase, or tyrosine kinase signaling pathways. Dominant-negative forms of Ras and/or Rac-1 significantly suppressed HIF-1 activation by muscarinic signaling. Signaling via M1- and M3- but not M2- or M4-AchRs promote accumulation and transcriptional activation of HIF-1alpha. We conclude that muscarinic acetylcholine signals activate HIF-1 by both stabilization and synthesis of HIF-1alpha and by inducing the transcriptional activity of HIF-1alpha.