Hypoxia-activated autophagy accelerates degradation of SQSTM1/p62
- 20 October 2008
- journal article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 28 (3), 334-344
- https://doi.org/10.1038/onc.2008.392
Abstract
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.Keywords
This publication has 45 references indexed in Scilit:
- Mitochondrial Autophagy Is an HIF-1-dependent Adaptive Metabolic Response to HypoxiaJournal of Biological Chemistry, 2008
- Autophagy fights disease through cellular self-digestionNature, 2008
- Autophagy in the Pathogenesis of DiseaseCell, 2008
- BNIP3 Is an RB/E2F Target Gene Required for Hypoxia-Induced AutophagyMolecular and Cellular Biology, 2007
- Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4The EMBO Journal, 2007
- Cerebral Ischemia-Hypoxia Induces Intravascular Coagulation and AutophagyThe American Journal of Pathology, 2006
- The signaling adapter p62 is an important mediator of T helper 2 cell function and allergic airway inflammationThe EMBO Journal, 2006
- The role of autophagy in cancer development and response to therapyNature Reviews Cancer, 2005
- Regulation of angiogenesis by hypoxia: role of the HIF systemNature Medicine, 2003
- LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processingThe EMBO Journal, 2000