Gadd45a and Gadd45b protect hematopoietic cells from UV-induced apoptosis via distinct signaling pathways, including p38 activation and JNK inhibition.
Gadd45a, Gadd45b, and Gadd45g (Gadd45/MyD118/CR6) are genes that are rapidly induced by genotoxic stress and have been implicated in genotoxic stress-induced responses, notably in apoptosis. Recently, using myeloid-enriched bone marrow (BM) cells obtained from wild-type (WT), Gadd45a-deficient, and Gadd45b-deficient mice, we have shown that in hematopoietic cells Gadd45a and Gadd45b play a survival function to protect hematopoietic cells from DNA-damaging agents, including ultra violet (UV)-induced apoptosis. The present study was undertaken to decipher the molecular paths that mediate the survival functions of Gadd45a and Gadd45b against genotoxic stress induced by UV radiation. It is shown that in hematopoietic cells exposed to UV radiation Gaddd45a and Gadd45b cooperate to promote cell survival via two distinct signaling pathways involving activation of the GADD45a-p38-NF-kappaB-mediated survival pathway and GADD45b-mediated inhibition of the stress response MKK4-JNK pathway.
Gupta
Mamta
M
Fels Institute of Cancer Research and Molecular Biology and Department of Biochemistry, Temple University School of Medicine, 3307 N. Broad Street, Philadelphia, PA 19140, USA.
Gupta
Shiv Kumar
SK
Hoffman
Barbara
B
Liebermann
Dan A
DA
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D004789:Enzyme Activation / Q000502:physiology / Q000528:radiation effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D022423:Myeloid Cells / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009687:Nuclear Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C490125:Gadd45b protein, mouse