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.
Xia
Yun
Y
Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore.
Ongusaha
Pat
P
Lee
Sam W
SW
Liou
Yih-Cherng
YC
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D053222:Fas Ligand Protein / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D018384:Oxidative Stress; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D000071636:Protein Phosphatase 2C; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019311:Staurosporine / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; D019384:Nucleic Acid Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D000841:Anisomycin; D005047:Etoposide; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; C000607468:Ppm1d protein, mouse; D000071636:Protein Phosphatase 2C; D019311:Staurosporine