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Title: NF-κB-dependent transcriptional upregulation of cyclin D1 exerts cytoprotection against hypoxic injury upon EGFR activation

Abstract

Apoptosis of neural cells is one of the main pathological features in hypoxic/ischemic brain injury. Nuclear factor-κB (NF-κB) might be a potential therapeutic target for hypoxic/ischemic brain injury since NF-κB has been found to be inactivated after hypoxia exposure, yet the underlying molecular mechanisms of NF-κB inactivation are largely unknown. Here we report that epidermal growth factor receptor (EGFR) activation prevents neuron-like PC12 cells apoptosis in response to hypoxia via restoring NF-κB-dependent transcriptional upregulation of cyclin D1. Functionally, EGFR activation by EGF stimulation mitigates hypoxia-induced PC12 cells apoptosis in both dose- and time-dependent manner. Of note, EGFR activation elevates IKKβ phosphorylation, increases IκBα ubiquitination, promotes P65 nuclear translocation and recruitment at cyclin D1 gene promoter as well as upregulates cyclin D1 expression. EGFR activation also abrogates the decrease of IKKβ phosphorylation, reduction of IκBα ubiquitination, blockade of P65 nuclear translocation and recruitment at cyclin D1 gene promoter as well as downregulation of cyclin D1 expression induced by hypoxia. Furthermore, NF-κB-dependent upregulation of cyclin D1 is instrumental for the EGFR-mediated cytoprotection against hypoxic apoptosis. In addition, the dephosphorylation of EGFR induced by either EGF siRNA transfection or anti-HB-EGF neutralization antibody treatment enhances hypoxic cytotoxicity, which are attenuated by EGF administration. Ourmore » results highlight the essential role of NF-κB-dependent transcriptional upregulation of cyclin D1 in EGFR-mediated cytoprotective effects under hypoxic preconditioning and support further investigation of EGF in clinical trials of patients with hypoxic/ischemic brain injury. - Highlights: • EGFR activation significantly decreases hypoxia-induced PC12 cells injury. • EGFR activation abrogates the transcriptional repression of cyclin D1 induced by hypoxia in a NF-κB-dependent manner. • NF-κB-dependent cyclin D1 upregulation is required for the EGFR-mediated cytoprotection against hypoxia-induced injury. • Endogenous EGFR activity antagonizes hypoxia-induced PC12 cells injury.« less

Authors:
 [1];  [2];  [1]; ; ; ; ; ; ; ;  [2];  [2];  [2]
  1. Department of Critical Care Medicine, The First Affiliated Hospital of Huzhou Normal College, Huzhou 313000, Zhejiang (China)
  2. Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, Hangzhou 310000, Zhejiang (China)
Publication Date:
OSTI Identifier:
22649754
Resource Type:
Journal Article
Resource Relation:
Journal Name: Experimental Cell Research; Journal Volume: 347; Journal Issue: 1; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ADMINISTRATIVE PROCEDURES; ANOXIA; ANTIBODIES; APOPTOSIS; BRAIN; CLINICAL TRIALS; DOSES; GENES; GROWTH FACTORS; INJURIES; ISCHEMIA; NERVE CELLS; PHOSPHORYLATION; PHOSPHOTRANSFERASES; PLANT GROWTH; PROMOTERS; RECEPTORS; STIMULATION; TIME DEPENDENCE; TOXICITY; TRANSCRIPTION; TRANSLOCATION

Citation Formats

Chen, Zhi-Dong, Xu, Liang, Tang, Kan-Kai, Gong, Fang-Xiao, Liu, Jing-Quan, Ni, Yin, Jiang, Ling-Zhi, Hong, Jun, Han, Fang, Li, Qian, Yang, Xiang-Hong, Sun, Ren-Hua, E-mail: jqin168@hotmail.com, and Mo, Shi-Jing, E-mail: msj860307@163.com. NF-κB-dependent transcriptional upregulation of cyclin D1 exerts cytoprotection against hypoxic injury upon EGFR activation. United States: N. p., 2016. Web. doi:10.1016/J.YEXCR.2016.07.004.
Chen, Zhi-Dong, Xu, Liang, Tang, Kan-Kai, Gong, Fang-Xiao, Liu, Jing-Quan, Ni, Yin, Jiang, Ling-Zhi, Hong, Jun, Han, Fang, Li, Qian, Yang, Xiang-Hong, Sun, Ren-Hua, E-mail: jqin168@hotmail.com, & Mo, Shi-Jing, E-mail: msj860307@163.com. NF-κB-dependent transcriptional upregulation of cyclin D1 exerts cytoprotection against hypoxic injury upon EGFR activation. United States. doi:10.1016/J.YEXCR.2016.07.004.
Chen, Zhi-Dong, Xu, Liang, Tang, Kan-Kai, Gong, Fang-Xiao, Liu, Jing-Quan, Ni, Yin, Jiang, Ling-Zhi, Hong, Jun, Han, Fang, Li, Qian, Yang, Xiang-Hong, Sun, Ren-Hua, E-mail: jqin168@hotmail.com, and Mo, Shi-Jing, E-mail: msj860307@163.com. 2016. "NF-κB-dependent transcriptional upregulation of cyclin D1 exerts cytoprotection against hypoxic injury upon EGFR activation". United States. doi:10.1016/J.YEXCR.2016.07.004.
@article{osti_22649754,
title = {NF-κB-dependent transcriptional upregulation of cyclin D1 exerts cytoprotection against hypoxic injury upon EGFR activation},
author = {Chen, Zhi-Dong and Xu, Liang and Tang, Kan-Kai and Gong, Fang-Xiao and Liu, Jing-Quan and Ni, Yin and Jiang, Ling-Zhi and Hong, Jun and Han, Fang and Li, Qian and Yang, Xiang-Hong and Sun, Ren-Hua, E-mail: jqin168@hotmail.com and Mo, Shi-Jing, E-mail: msj860307@163.com},
abstractNote = {Apoptosis of neural cells is one of the main pathological features in hypoxic/ischemic brain injury. Nuclear factor-κB (NF-κB) might be a potential therapeutic target for hypoxic/ischemic brain injury since NF-κB has been found to be inactivated after hypoxia exposure, yet the underlying molecular mechanisms of NF-κB inactivation are largely unknown. Here we report that epidermal growth factor receptor (EGFR) activation prevents neuron-like PC12 cells apoptosis in response to hypoxia via restoring NF-κB-dependent transcriptional upregulation of cyclin D1. Functionally, EGFR activation by EGF stimulation mitigates hypoxia-induced PC12 cells apoptosis in both dose- and time-dependent manner. Of note, EGFR activation elevates IKKβ phosphorylation, increases IκBα ubiquitination, promotes P65 nuclear translocation and recruitment at cyclin D1 gene promoter as well as upregulates cyclin D1 expression. EGFR activation also abrogates the decrease of IKKβ phosphorylation, reduction of IκBα ubiquitination, blockade of P65 nuclear translocation and recruitment at cyclin D1 gene promoter as well as downregulation of cyclin D1 expression induced by hypoxia. Furthermore, NF-κB-dependent upregulation of cyclin D1 is instrumental for the EGFR-mediated cytoprotection against hypoxic apoptosis. In addition, the dephosphorylation of EGFR induced by either EGF siRNA transfection or anti-HB-EGF neutralization antibody treatment enhances hypoxic cytotoxicity, which are attenuated by EGF administration. Our results highlight the essential role of NF-κB-dependent transcriptional upregulation of cyclin D1 in EGFR-mediated cytoprotective effects under hypoxic preconditioning and support further investigation of EGF in clinical trials of patients with hypoxic/ischemic brain injury. - Highlights: • EGFR activation significantly decreases hypoxia-induced PC12 cells injury. • EGFR activation abrogates the transcriptional repression of cyclin D1 induced by hypoxia in a NF-κB-dependent manner. • NF-κB-dependent cyclin D1 upregulation is required for the EGFR-mediated cytoprotection against hypoxia-induced injury. • Endogenous EGFR activity antagonizes hypoxia-induced PC12 cells injury.},
doi = {10.1016/J.YEXCR.2016.07.004},
journal = {Experimental Cell Research},
number = 1,
volume = 347,
place = {United States},
year = 2016,
month = 9
}
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