Cell cycle promoting activity of JunB through cyclin A activation.
JunB, a major component of the AP-1 transcription factor, is known to act antagonistically to c-Jun in transcriptional regulation and is proposed to be a negative regulator of cell proliferation. Employing fibroblasts derived from E9.5 junB(-/-) mouse embryos we provide evidence for a novel cell cycle promoting role of JunB. Despite a normal proliferation rate, primary and immortalized junB(-/-) fibroblasts exhibited an altered cell cycle profile, which was characterized by an increase in the population of S-phase cells, while that of cells in G(2)/M-phase was diminished. This delay in G(2)/M-transition is caused by impaired cyclin A-CDK2 and cyclin B-CDC2 kinase activities and counteracts the accelerated S-phase entry. Cells lacking JunB show severely delayed kinetics of cyclin A mRNA expression due to the loss of proper transcriptional activation mediated via binding of JunB to the CRE element in the cyclin A promoter. Upon reintroduction of an inducible JunB-ER(TM) expression vector the cell cycle distribution and the cell cycle-associated cyclin A-CDK2 kinase activity could be restored. Thus, cyclin A is a direct transcriptional target of JunB driving cell proliferation.
Division for Signal Transduction and Growth Control, Deutsches Krebsforschungszentrum Heidelberg, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Sven
S
Andrecht
Andrea
A
Kolbus
Bettina
B
Hartenstein
Peter
P
Angel
Marina
M
Schorpp-Kistner
D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division; D019925:Cyclin A / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D016195:G2 Phase; D017930:Genes, Reporter; D005822:Genetic Vectors; D051379:Mice; D008938:Mitosis; D008954:Models, Biological; D008957:Models, Genetic; D010766:Phosphorylation; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016196:S Phase; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic
D019925:Cyclin A; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D011494:Protein Kinases; C102333:histone H1 kinase