Selective activation of p38α and p38γ by hypoxia -: Role in regulation of cyclin D1 by hypoxia in PC12 cells
Selective activation of p38α and p38γ by hypoxia -: Role in regulation of cyclin D1 by hypoxia in PC12 cells
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DOI：
10.1074/jbc.274.33.23570
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发表时间：
1999-08-13
影响因子：
4.8
通讯作者：
Beitner-Johnson, D
中科院分区：
文献类型：
--
作者：
Conrad, PW;Rust, RT;Beitner-Johnson, D
缺氧/缺血性损伤是多种疾病病理过程中的主要因素，我们在PC12细胞中研究了缺氧对应激和丝裂原激活蛋白激酶信号通路的影响。中度低氧(5%O-2)可明显刺激p38-γ和p38α两种应激激活蛋白激酶的磷酸化和活化，而低氧对p38β、p38β(2)、p38 Delta和另一应激激活蛋白激酶c-jun氨基末端激酶的活性无明显影响。长时间的低氧也诱导了p42/p44丝裂原活化蛋白激酶的磷酸化和激活，尽管与神经生长因子和紫外线诱导的激活相比，这种激活是温和的。低氧还显著下调细胞周期蛋白D1的免疫反应性，该基因已知在基因表达水平上受p38的负调控(Lavie，J，N.，L‘Allemain，G，，Brunet，A.，Muller，R.和Pouyssegur，J.(1996)J.Biol)。化学。271、20608-20616)。这一作用可被p38α的抑制剂SB203580部分阻断，但不能阻断p38伽马的这一作用。p38伽马的过表达也能够部分逆转缺氧对细胞周期蛋白D1水平的影响，这表明p38α和p38伽马在缺氧过程中会聚在一起调节细胞周期蛋白D1。这些研究表明，极端典型的生理应激(缺氧)导致特定的p38信号元件选择性激活；它们还识别了这些信号通路的下游靶点。
Hypoxic/ischemic trauma is a primary factor in the pathology of a multitude of disease states, The effects of hypoxia on the stress- and mitogen-activated protein kinase signaling pathways were studied in PC12 cells. Exposure to moderate hypoxia (5% O-2) progressively stimulated phosphorylation and activation of p38 gamma in particular, and also p38 alpha, two stress-activated protein kinases, In contrast, hypoxia had no effect on enzyme activity of p38 beta, p38 beta(2), p38 delta, or on c-Jun N-terminal kinase, another stress-activated protein kinase. Prolonged hypoxia also induced phosphorylation and activation of p42/p44 mitogen-activated protein kinase, although this activation was modest compared with nerve growth factor- and ultraviolet light-induced activation. Hypoxia also dramatically down-regulated immunoreactivity of cyclin D1, a gene that is known to be regulated negatively by p38 at the level of gene expression (Lavoie, J, N., L'Allemain, G,, Brunet, A., Muller, R., and Pouyssegur, J. (1996) J. Biol. Chem. 271, 20608-20616). This effect was partially blocked by SB203580, an inhibitor of p38 alpha but not p38 gamma, Overexpression of a kinase-inactive form of p38 gamma was also able to reverse in part the effect of hypoxia on cyclin D1 levels, suggesting that p38 alpha and p38 gamma converge to regulate cyclin D1 during hypoxia, These studies demonstrate that an extremely typical physiological stress (hypoxia) causes selective activation of specific p38 signaling elements; and they also identify a downstream target of these pathways.