Antagonistic control of cell fates by JNK and p38-MAPK signaling.
During the development and organogenesis of all multicellular organisms, cell fate decisions determine whether cells undergo proliferation, differentiation, or aging. Two independent stress kinase signaling pathways, p38-MAPK, and JNKs, have evolved that relay developmental and environmental cues to determine cell responses. Although multiple stimuli can activate these two stress kinase pathways, the functional interactions and molecular cross-talks between these common second signaling cascades are poorly elucidated. Here we report that JNK and p38-MAPK pathways antagonistically control cellular senescence, oncogenic transformation, and proliferation in primary mouse embryonic fibroblasts (MEFs). Similarly, genetic inactivation of the JNK pathway results in impaired proliferation of fetal hepatoblasts in vitro and defective adult liver regeneration in vivo, which is rescued by inhibition of the p38-MAPK pathway. Thus, the balance between the two stress-signaling pathways, MKK7-JNK and MKK3/6-p38-MAPK, determines cell fate and links environmental and developmental stress to cell cycle arrest, senescence, oncogenic transformation, and adult tissue regeneration.
Wada
T
T
IMBA: Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 3, Vienna, Austria.
Stepniak
E
E
Hui
L
L
Leibbrandt
A
A
Katada
T
T
Nishina
H
H
Wagner
E F
EF
Penninger
J M
JM
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016922:Cellular Senescence; D005347:Fibroblasts / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008115:Liver Regeneration; D020935:MAP Kinase Signaling System; D051379:Mice; D008817:Mice, Mutant Strains; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016203:CDC2 Protein Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases