MKK7 couples stress signalling to G2/M cell-cycle progression and cellular senescence.
During the development of multicellular organisms, concerted actions of molecular signalling networks determine whether cells undergo proliferation, differentiation, death or ageing. Here we show that genetic inactivation of the stress signalling kinase, MKK7, a direct activator of JNKs in mice, results in embryonic lethality and impaired proliferation of hepatocytes. Beginning at passage 4-5, mkk7(-/-) mouse embryonic fibroblasts (MEFs) display impaired proliferation, premature senescence and G2/M cell cycle arrest. Similarly, loss of c-Jun or expression of a c-JunAA mutant in which the JNK phosphorylation sites were replaced with alanine results in a G2/M cell-cycle block. The G2/M cell-cycle kinase CDC2 was identified as a target for the MKK7-JNK-c-Jun pathway. These data show that the MKK7-JNK-c-Jun signalling pathway couples developmental and environmental cues to CDC2 expression, G2/M cell cycle progression and cellular senescence in fibroblasts.
Wada
Teiji
T
Institute of Molecular Biotechnology of the Austrian Academy of Sciences, c/o Dr. Bohrgasse 3-5, A-1030 Vienna, Austria.
Joza
Nicholas
N
Cheng
Hai-ying M
HY
Sasaki
Takehiko
T
Kozieradzki
Ivona
I
Bachmaier
Kurt
K
Katada
Toshiaki
T
Schreiber
Martin
M
Wagner
Erwin F
EF
Nishina
Hiroshi
H
Penninger
Josef M
JM
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics*; D005333:Fetus; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D016195:G2 Phase / Q000235:genetics*; D005804:Genes, Lethal / Q000235:genetics; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology*; D048031:JNK Mitogen-Activated Protein Kinases; D008099:Liver / Q000002:abnormalities / Q000473:pathology; D048688:MAP Kinase Kinase 7; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000172:deficiency* / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008938:Mitosis / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000172:deficiency / Q000235:genetics; D013312:Stress, Physiological / Q000201:enzymology* / Q000235:genetics
D018797:Cell Cycle Proteins; D016755:Proto-Oncogene Proteins c-jun; D016203:CDC2 Protein Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048688:MAP Kinase Kinase 7; C482570:Map2k7 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases