Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest.
The p38 group of kinases belongs to the mitogen-activated protein (MAP) kinase superfamily with structural and functional characteristics distinguishable from those of the ERK, JNK (SAPK), and BMK (ERK5) kinases. Although there is a high degree of similarity among members of the p38 group in terms of structure and activation, each member appears to have a unique function. Here we show that activation of p38gamma (also known as ERK6 or SAPK3), but not the other p38 isoforms, is required for gamma-irradiation-induced G(2) arrest. Activation of the MKK6-p38gamma cascade is sufficient to induce G(2) arrest in cells, and expression of dominant negative alleles of MKK6 or p38gamma allows cells to escape the DNA damage-induce G(2) delay. Activation of p38gamma is dependent on ATM and leads to activation of Cds1 (also known as Chk2). These data suggest a model in which activation of ATM by gamma irradiation leads to the activation of MKK6, p38gamma, and Cds1 and that activation of both MKK6 and p38gamma is essential for the proper regulation of the G(2) checkpoint in mammalian cells.
Wang
X
X
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
McGowan
C H
CH
Zhao
M
M
He
L
L
Downey
J S
JS
Fearns
C
C
Wang
Y
Y
Huang
S
S
Han
J
J
D064007:Ataxia Telangiectasia Mutated Proteins; D016203:CDC2 Protein Kinase / Q000187:drug effects / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects*; D002453:Cell Cycle / Q000528:radiation effects*; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000528:radiation effects; D016923:Cell Death / Q000528:radiation effects; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000528:radiation effects; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000528:radiation effects; D016195:G2 Phase / Q000528:radiation effects; D005720:Gamma Rays; D006367:HeLa Cells / Q000528:radiation effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007527:Isoenzymes; D048369:MAP Kinase Kinase 1; D048671:MAP Kinase Kinase 5; D048669:MAP Kinase Kinase 6; D048688:MAP Kinase Kinase 7; D048054:Mitogen-Activated Protein Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins; D020687:cdc25 Phosphatases / Q000378:metabolism / Q000528:radiation effects; D048051:p38 Mitogen-Activated Protein Kinases
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007527:Isoenzymes; D011725:Pyridines; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016203:CDC2 Protein Kinase; D048054:Mitogen-Activated Protein Kinase 7; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048671:MAP Kinase Kinase 5; D048669:MAP Kinase Kinase 6; D048688:MAP Kinase Kinase 7; C482125:MAP2K1 protein, human; C482563:MAP2K5 protein, human; C482566:MAP2K6 protein, human; C482569:MAP2K7 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases; C093642:SB 203580