Pursiheimo J-P, Rantanen K, Heikkinen P T, Johansen T, Jaakkola P M
Turku Centre for Biotechnology, Turku University and Abo Akademi University, Turku, Finland.
Oncogene. 2009 Jan 22;28(3):334-44. doi: 10.1038/onc.2008.392. Epub 2008 Oct 20.
Sequestosome 1 (SQSTM1/p62) is a multifunctional protein involved in signal transduction, protein degradation and cell transformation. Hypoxia is a common feature of solid tumours that promotes cancer progression. Here, we report that p62 is downregulated in hypoxia in carcinoma cells and that the expression is rapidly restored in response to reoxygenation. The hypoxic p62 downregulation did not occur at the mRNA level and was independent of the hypoxic signal mediators hypoxia-inducible factor (HIF) and von Hippel-Lindau tumour suppressor protein as well as the activity of HIF-prolyl hydroxylases and was not mediated by proteosomal destruction. Autophagy was activated in hypoxia and was required for p62 degradation. The hypoxic degradation of p62 was blocked by autophagy inhibitors as well as by the attenuation of Atg8/LC3 expression. Downregulation of p62 was required for hypoxic extracellular regulated kinase (ERK)-1/2 phosphorylation. Attenuation of p62 in normoxia activated and forced expression of p62 in hypoxia blocked the activation of ERK-1/2. The results demonstrate that hypoxic activation of autophagy induces clearance of p62 protein and implies a role for p62 in the regulation of hypoxic cancer cell survival responses.
聚集体蛋白1（SQSTM1/p62）是一种多功能蛋白，参与信号转导、蛋白质降解和细胞转化。缺氧是实体瘤的一个常见特征，可促进癌症进展。在此，我们报告p62在癌细胞缺氧时下调，并且其表达在复氧后迅速恢复。缺氧时p62的下调并非发生在mRNA水平，且独立于缺氧信号介质缺氧诱导因子（HIF）和冯·希佩尔-林道肿瘤抑制蛋白，也与HIF-脯氨酰羟化酶的活性无关，并且不是由蛋白酶体破坏介导的。自噬在缺氧时被激活，并且是p62降解所必需的。p62的缺氧降解被自噬抑制剂以及Atg8/LC3表达的减弱所阻断。缺氧时细胞外调节激酶（ERK）-1/2磷酸化需要p62的下调。常氧下p62的减弱激活以及缺氧时p62的强制表达阻断了ERK-1/2的激活。结果表明，自噬的缺氧激活诱导p62蛋白的清除，并暗示p62在缺氧癌细胞存活反应的调节中起作用。
