title: CRHR1 mediates p53 transcription induced by high altitude hypoxia through ERK 1/2 signaling in rat hepatic cells.
abstract: We have previously reported that hypoxia activates corticotrophin-releasing hormone (CRH) and the expression of its type-1 receptor (CRHR1) and induces disorders of the brain-endocrine-immune network. p53 is activated by hypoxia and involved in tumorigenesis and apoptosis. Whether CRHR1 regulates p53 transactivation to further influence apoptotic genes remains unclear. Here, we showed that hypoxia at a simulated altitude of 5km or 7km for 8 and 24h increased p53 protein and mRNA, and reduced apoptotic bax and IGFBP3 gene expression while upregulating the cell-arrest gene p21 for 8h in rat liver cells. The upregulation of p53 mRNA and downregulation of bax mRNA induced by hypoxia were blocked by pretreatment with the specific CRHR1 antagonist CP-154,526, but the downregulation of IGFBP3 and upregulation of p21 mRNA were not. Furthermore, CRH stimulated p53 mRNA via the ERK 1/2 pathway in the BRL-3A cell line and this was blocked by the ERK 1/2 antagonist U0126. These data provide novel evidence that the CRHR1-triggered ERK 1/2 pathway is involved in the activation of p53 and suppression of the apoptotic bax gene by hypoxia in rat liver.
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ming-Yang
authors.initials: MY
authors.lastname: Wang
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.forename: Xue-Qun
authors.initials: XQ
authors.lastname: Chen
authors.forename: Ji-Zeng
authors.initials: JZ
authors.lastname: Du
mesh_terms: D000531:Altitude; D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D022781:Hepatocytes / Q000378:metabolism*; D000860:Hypoxia / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D016159:Tumor Suppressor Protein p53; D000099052:CRF Receptor, Type 1