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. 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.
authors.affiliation: Department of Critical Care Medicine, The First Affiliated Hospital of Huzhou Normal College, Huzhou 313000, Zhejiang, China.
authors.forename: Zhi-Dong
authors.initials: ZD
authors.lastname: Chen
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Critical Care Medicine, The First Affiliated Hospital of Huzhou Normal College, Huzhou 313000, Zhejiang, China.
authors.forename: Kan-Kai
authors.initials: KK
authors.lastname: Tang
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang, China.
authors.forename: Fang-Xiao
authors.initials: FX
authors.lastname: Gong
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang, China.
authors.forename: Jing-Quan
authors.initials: JQ
authors.lastname: Liu
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang, China.
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Jiang
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Han
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang, China.
authors.forename: Xiang-Hong
authors.initials: XH
authors.lastname: Yang
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang, China. Electronic address: jqin168@hotmail.com.
authors.forename: Ren-Hua
authors.initials: RH
authors.lastname: Sun
authors.affiliation: Department of Critical Care Medicine, Zhejiang Provincial People's Hospital, Hangzhou 310000, Zhejiang, China. Electronic address: msj860307@163.com.
authors.forename: Shi-Jing
authors.initials: SJ
authors.lastname: Mo
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D019610:Cytoprotection / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D016716:PC12 Cells; D011401:Promoter Regions, Genetic; D051381:Rats; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D016328:NF-kappa B; D019938:Cyclin D1; D066246:ErbB Receptors
keywords: Cyclin D1; Epidermal growth factor receptor; Hypoxia; Injury; Nuclear factor-κB