Loss of Wip1 Sensitizes Cells to Stress- and DNA Damage-induced Apoptosis
Copyright policy )Loss of Wip1 Sensitizes Cells to Stress- and DNA Damage-induced Apoptosis
In response to various environmental stresses, the stress-responsive MAPKs p38 and JNK are activated and phosphorylate ATF2 and c-Jun transcription factors, thereby affecting cell-fate decision. Targeted gene disruption studies have established that JNK-c-Jun signaling plays a vital role in stress-induced apoptosis. The oncogenic phosphatase Wip1 acts as an important regulator in DNA damage pathway by dephosphorylating a spectrum of proteins including p53, p38, Chk1, Chk2, and ATM. In this study we show that Wip1 negatively regulates the activation of MKK4-JNK-c-Jun signaling during stress-induced apoptosis. The loss of Wip1 function sensitizes mouse embryonic fibroblasts to stress-induced apoptosis via the activation of both p38-ATF2 and JNK-c-Jun signaling. Here we reveal that Wip1 has dual roles in alternatively regulating stress- and DNA damage-induced apoptosis through p38/JNK MAPKs and p38/p53-dependent pathways, respectively. Our results point to Wip1 as a general regulator of apoptosis, which further supports its role in tumorigenesis.
- Harvard University United States
- National University of Singapore Libraries Singapore
- National University of Singapore Singapore
Mice, Knockout, Fas Ligand Protein, Immunoblotting, JNK Mitogen-Activated Protein Kinases, 610, Apoptosis, Hydrogen Peroxide, Fibroblasts, Embryo, Mammalian, MAP Kinase Kinase Kinases, Antineoplastic Agents, Phytogenic, Mice, Oxidative Stress, Phosphoprotein Phosphatases, Animals, Enzyme Inhibitors, Anisomycin, Cells, Cultured, DNA Damage, Etoposide, Nucleic Acid Synthesis Inhibitors
Mice, Knockout, Fas Ligand Protein, Immunoblotting, JNK Mitogen-Activated Protein Kinases, 610, Apoptosis, Hydrogen Peroxide, Fibroblasts, Embryo, Mammalian, MAP Kinase Kinase Kinases, Antineoplastic Agents, Phytogenic, Mice, Oxidative Stress, Phosphoprotein Phosphatases, Animals, Enzyme Inhibitors, Anisomycin, Cells, Cultured, DNA Damage, Etoposide, Nucleic Acid Synthesis Inhibitors
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