MKK7 couples stress signalling to G2/M cell-cycle progression and cellular senescence

• DOI: 10.1038/ncb1098
• Publication Date: 2004-03-01T15:00:32Z
• Authors: Teiji Wada; Nicholas Joza; Hai-ying M. Cheng; Takehiko Sasaki; Ivona Kozieradzki; Kurt Bachmaier; Toshiaki Katada; Martin Schreiber; Erwin F. Wagner; Hiroshi Nishina; Josef M. Penninger
• Keywords: G2 Phase; Mitogen-Activated Protein Kinase Kinases; 0301 basic medicine; MAP Kinase Signaling System; JNK Mitogen-Activated Protein Kinases; Mitosis; Cell Cycle Proteins; MAP Kinase Kinase 7; Fibroblasts; Mice; 03 medical and health sciences; Fetus; Liver; CDC2 Protein Kinase; Mutation; Hepatocytes; Animals; Genes, Lethal; Mitogen-Activated Protein Kinases; Phosphorylation; Cells, Cultured; 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.