Loss of oncogenic H-ras-induced cell cycle arrest and p38 mitogen-activated protein kinase activation by disruption of Gadd45a.
The activation of p53 is a guardian mechanism to protect primary cells from malignant transformation; however, the details of the activation of p53 by oncogenic stress are still incomplete. In this report we show that in Gadd45a(-/-) mouse embryo fibroblasts (MEF), overexpression of H-ras activates extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) but not p38 kinase, and this correlates with the loss of H-ras-induced cell cycle arrest (premature senescence). Inhibition of p38 mitogen-activated protein kinase (MAPK) activation correlated with the deregulation of p53 activation, and both a p38 MAPK chemical inhibitor and the expression of a dominant-negative p38alpha inhibited p53 activation in the presence of H-ras in wild-type MEF. p38, but not ERK or JNK, was found in a complex with Gadd45 proteins. The region of interaction was mapped to amino acids 71 to 96, and the central portion (amino acids 71 to 124) of Gadd45a was required for p38 MAPK activation in the presence of H-ras. Our results indicate that this Gadd45/p38 pathway plays an important role in preventing oncogene-induced growth at least in part by regulating the p53 tumor suppressor.
Gene Response Section, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA.
Dmitry V
DV
Bulavin
Oleg
O
Kovalsky
M Christine
MC
Hollander
Albert J
AJ
Fornace
D000818:Animals; D001665:Binding Sites; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D011905:Genes, ras; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D048051:p38 Mitogen-Activated Protein Kinases; C493957:Cdkn1a protein, mouse; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins