title: GADD45α induction by nickel negatively regulates JNKs/p38 activation via promoting PP2Cα expression.
abstract: Growth arrest and DNA damage (GADD) 45α is a member of GADD inducible gene family, and is inducible in cell response to oxidative stress. GADD45α upregulation induces MKK4/JNK activation in some published experimental systems. However, we found here that the depletion of GADD45α (GADD45α-/-) in mouse embryonic fibroblasts (MEFs) resulted in an increase in the phosphorylation of MKK4/7, MKK3/6 and consequently specific up-regulated the activation of JNK/p38 and their downstream transcription factors, such as c-Jun and ATF2, in comparison to those in GADD45α+/+ MEFs cell following nickel exposure. This up-regulation of MKK-JNK/p38 pathway in GADD45α-/- cell could be rescued by the reconstitutional expression of HA-GADD45α in GADD45α-/- MEFs, GADD45α-/-(HA-GADD45α). Subsequent studies indicated that GADD45α deletion repressed expression of PP2Cα, the phosphotase of MKK3/6 and MKK4/7, whereas ectopic expression of HA-PP2Cα in GADD45α-/- cells attenuated activation of MKK3/6-p38 and MKK4/7-JNK pathways. Collectively, our results demonstrate a novel function and mechanism responsible for GADD45α regulation of MKK/MAPK pathway, further provides insight into understanding the big picture of GADD45α in the regulation of cellular responses to oxidative stress and environmental carcinogens.
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, United States of America.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Yu
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Wan
authors.forename: Jianyi
authors.initials: J
authors.lastname: Lu
authors.forename: Jimin
authors.initials: J
authors.lastname: Gao
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009532:Nickel / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D000071636:Protein Phosphatase 2C; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D009532:Nickel; D009687:Nuclear Proteins; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D018808:Transcription Factor AP-1; D048051:p38 Mitogen-Activated Protein Kinases; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins
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