State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Burn Research, Southwest Hospital, The Third Military Medical University, 400038, Chongqing, People's Republic of China.
Cell Mol Life Sci. 2010 Jan;67(2):321-33. doi: 10.1007/s00018-009-0187-z. Epub 2009 Nov 14.
In both cardiomyocytes and HeLa cells, hypoxia (1% O(2)) quickly leads to microtubule disruption, but little is known about how microtubule dynamics change during the early stages of hypoxia. We demonstrate that microtubule associated protein 4 (MAP4) phosphorylation increases while oncoprotein 18/stathmin (Op18) phosphorylation decreases after hypoxia, but their protein levels do not change. p38/MAPK activity increases quickly after hypoxia concomitant with MAP4 phosphorylation, and the activated p38/MAPK signaling leads to MAP4 phosphorylation and to Op18 dephosphorylation, both of which induce microtubule disruption. We confirmed the interaction between phospho-p38 and MAP4 using immunoprecipitation and found that SB203580, a p38/MAPK inhibitor, increases and MKK6(Glu) overexpression decreases hypoxic cell viability. Our results demonstrate that hypoxia induces microtubule depolymerization and decreased cell viability via the activation of the p38/MAPK signaling pathway and changes the phosphorylation levels of its downstream effectors, MAP4 and Op18.
在心肌细胞和 HeLa 细胞中，缺氧（1% O(2)) 很快导致微管解体，但对于缺氧早期微管动力学的变化知之甚少。我们证明，缺氧后微管相关蛋白 4 (MAP4) 的磷酸化增加，而癌蛋白 18/微管稳定蛋白 (Op18) 的磷酸化减少，但它们的蛋白水平没有变化。缺氧后 p38/MAPK 活性迅速增加，伴随着 MAP4 磷酸化，激活的 p38/MAPK 信号导致 MAP4 磷酸化和 Op18 去磷酸化，这两者都诱导微管解体。我们使用免疫沉淀证实了磷酸化 p38 和 MAP4 之间的相互作用，并发现 p38/MAPK 抑制剂 SB203580 增加，而 MKK6(Glu) 过表达减少缺氧细胞活力。我们的结果表明，缺氧通过激活 p38/MAPK 信号通路诱导微管解聚和细胞活力降低，并改变其下游效应物 MAP4 和 Op18 的磷酸化水平。
