Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation.
Different c-Jun N-terminal kinases (JNKs) are activated by a plethora of signals and phosphorylate substrates such as c-Jun, which is required for efficient cell cycle progression. Although JNK1 and JNK2 were shown to differentially regulate fibroblast proliferation, the underlying mechanistic basis remains unclear. We found that Jnk2-/- fibroblasts exit G1 and enter S phase earlier than wild-type counterparts, while Jnk1-/- cells show the inverse phenotype. Moreover, Jnk2-/- erythroblasts also exhibit a proliferative advantage. JNK2 deficiency results in elevated c-Jun phosphorylation and stability, whereas the absence of JNK1 reduces c-Jun phosphorylation and stability. Re-expression of JNK2 in Jnk2-/- cells reverses the JNK2 null phenotype, whereas ectopic expression of JNK1 augments it. JNK2 is preferentially bound to c-Jun in unstimulated cells, thereby contributing to c-Jun degradation. In contrast, JNK1 becomes the major c-Jun interacting kinase after cell stimulation. These data provide mechanistic insights into the distinct roles of different JNK isoforms.
Sabapathy
Kanaga
K
Research Institute of Molecular Pathology, Dr. Bohrgasse 7, A-1030 Vienna, Austria. cmrksb@nccs.com.sg
Hochedlinger
Konrad
K
Nam
Shin Yuen
SY
Bauer
Anton
A
Karin
Michael
M
Wagner
Erwin F
EF
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division / Q000235:genetics; D004789:Enzyme Activation / Q000502:physiology; D004900:Erythroblasts / Q000378:metabolism; D005333:Fetus; D005347:Fibroblasts / Q000378:metabolism; D016193:G1 Phase / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D016196:S Phase / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D020033:Protein Isoforms; D016755:Proto-Oncogene Proteins c-jun; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases