Title: GADD45α induction by nickel negatively regulates JNKs/p38 activation via promoting PP2Cα expression.
Authors: Yu, Yonghui; Li, Jingxia; Wan, Yu; Lu, Jianyi; Gao, Jimin; Huang, Chuanshu
Published In PLoS One, (2013)
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.
PubMed ID: 23536762
MeSH Terms: Animals; Cell Cycle Proteins/genetics; Cell Cycle Proteins/metabolism*; Cell Line; Enzyme Activation/drug effects; Gene Expression; Gene Expression Regulation/drug effects*; HCT116 Cells; Humans; JNK Mitogen-Activated Protein Kinases/metabolism*; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase Kinases/metabolism; Nickel/pharmacology*; Nuclear Proteins/genetics; Nuclear Proteins/metabolism*; Phosphoprotein Phosphatases/genetics*; Phosphoprotein Phosphatases/metabolism; Protein Phosphatase 2C; Signal Transduction/drug effects; Transcription Factor AP-1/metabolism; p38 Mitogen-Activated Protein Kinases/metabolism*