Abstract
Hypoxia/anoxia promotes tumor aggressiveness and negatively impacts tumor response to therapy. Coordinate regulation of HIF-dependent and HIF-independent pathways has been shown to contribute to cellular adaptation to hypoxic stress, and to couple macromolecular synthesis rates to reduced energy availability. An important component of this type of adaptation is the activation of the endoplasmic reticulum kinase PERK by acute or prolonged hypoxia. Activated PERK subsequently induces phosphorylation of the translation initiation factor eIF2α and translational upregulation of the transcription factor ATF4. ATF4 is a basic leucine-zipper (bZip) transcription factor, which regulates amino acid metabolism, cellular redox state, and antistress responses. ATF4 expression can be regulated at transcriptional, translational, and post-translational levels. The functional activation of ATF4 under hypoxia and the overexpression of ATF4 in hypoxic areas of clinical samples of human tumors suggest that ATF4 plays a role in tumor hypoxic adaptation. Here we summarize recent findings regarding the regulation of ATF4 in transformed cells, clinical tumor samples and tumor models, and speculate on its potential role in tumor progression and chemoresistance.
Current Molecular Medicine
Title: ATF4, an ER Stress and Hypoxia-Inducible Transcription Factor and its Potential Role in Hypoxia Tolerance and Tumorigenesis
Volume: 9 Issue: 4
Author(s): Jiangbin Ye and Constantinos Koumenis
Affiliation:
Keywords: ATF4, hypoxia, ER stress
Abstract: Hypoxia/anoxia promotes tumor aggressiveness and negatively impacts tumor response to therapy. Coordinate regulation of HIF-dependent and HIF-independent pathways has been shown to contribute to cellular adaptation to hypoxic stress, and to couple macromolecular synthesis rates to reduced energy availability. An important component of this type of adaptation is the activation of the endoplasmic reticulum kinase PERK by acute or prolonged hypoxia. Activated PERK subsequently induces phosphorylation of the translation initiation factor eIF2α and translational upregulation of the transcription factor ATF4. ATF4 is a basic leucine-zipper (bZip) transcription factor, which regulates amino acid metabolism, cellular redox state, and antistress responses. ATF4 expression can be regulated at transcriptional, translational, and post-translational levels. The functional activation of ATF4 under hypoxia and the overexpression of ATF4 in hypoxic areas of clinical samples of human tumors suggest that ATF4 plays a role in tumor hypoxic adaptation. Here we summarize recent findings regarding the regulation of ATF4 in transformed cells, clinical tumor samples and tumor models, and speculate on its potential role in tumor progression and chemoresistance.
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Cite this article as:
Ye Jiangbin and Koumenis Constantinos, ATF4, an ER Stress and Hypoxia-Inducible Transcription Factor and its Potential Role in Hypoxia Tolerance and Tumorigenesis, Current Molecular Medicine 2009; 9 (4) . https://dx.doi.org/10.2174/156652409788167096
DOI https://dx.doi.org/10.2174/156652409788167096 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |
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