HIF1-regulated ATRIP expression is required for hypoxia induced ATR activation

• Published in: FEBS letters Vol. 587; no. 7; pp. 930 - 935
• Main Authors: Ding, Gang, Liu, He-Dai, Liang, Hong-Xiang, Ni, Ru-Feng, Ding, Zhao-Yan, Ni, Guo-Ying, Hua, Hong-Wei, Xu, Wei-Guo
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 02.04.2013
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Ataxia Telangiectasia Mutated Proteins; ATR; ATRIP; Binding Sites - genetics; Blotting, Western; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Hypoxia; Cell Line; Checkpoint Kinase 1; Chromatin Immunoprecipitation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Expression Regulation, Neoplastic; HEK293 Cells; HeLa Cells; Hep G2 Cells; HIF-1; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; MCF-7 Cells; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Phosphorylation; Promoter Regions, Genetic - genetics; Protein Binding; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Response Elements - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; HIF-1; Hypoxia; ATRIP; ATR
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2013.02.020

► Hypoxia and hypoxia reagent induce ATRIP expression. ► HIF-1 mediates hypoxia-induced ATRIP expression. ► Identification and validation of a functional HRE in the ATRIP promoter region. ► Hypoxia-induced ATR activation is mediated by ATRIP. The ATR–ATRIP protein kinase complex plays a crucial role in the cellular response to replication stress and DNA damage. Recent studies found that ATR could be activated in response to hypoxia and be involved in hypoxia-induced genetic instability in cancer cells. However, the underlying mechanisms for ATR activation in response to hypoxic stress are still not fully understood. We reported that ATRIP is a direct target of HIF-1. Silencing the expression of HIF-1α in cancer cells by RNA interference abolished hypoxia-induced ATRIP expression. Silencing the expression of ATRIP by RNA interference abolished hypoxia induced ATR activation and CHK1 phosphorylation in cancer cells. Taken together, these data shed novel insights on the mechanism of hypoxia-induced activation of the ATR pathway.