GADD45α Induction by Nickel Negatively Regulates JNKs/p38 Activation via Promoting PP2Cα Expression
Copyright policy )GADD45α Induction by Nickel Negatively Regulates JNKs/p38 Activation via Promoting PP2Cα Expression
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.
- Wenzhou Medical University China (People's Republic of)
- New York University School of Medicine
- Wuhan University China (People's Republic of)
- New York University United States
Science, Gene Expression, Cell Cycle Proteins, p38 Mitogen-Activated Protein Kinases, Cell Line, Mice, Nickel, Phosphoprotein Phosphatases, Animals, Humans, Mice, Knockout, Mitogen-Activated Protein Kinase Kinases, Q, R, JNK Mitogen-Activated Protein Kinases, Nuclear Proteins, HCT116 Cells, Enzyme Activation, Protein Phosphatase 2C, Transcription Factor AP-1, Gene Expression Regulation, Medicine, Research Article, Signal Transduction
Science, Gene Expression, Cell Cycle Proteins, p38 Mitogen-Activated Protein Kinases, Cell Line, Mice, Nickel, Phosphoprotein Phosphatases, Animals, Humans, Mice, Knockout, Mitogen-Activated Protein Kinase Kinases, Q, R, JNK Mitogen-Activated Protein Kinases, Nuclear Proteins, HCT116 Cells, Enzyme Activation, Protein Phosphatase 2C, Transcription Factor AP-1, Gene Expression Regulation, Medicine, Research Article, Signal Transduction
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