Abstract
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.
Highlights
Eukaryotic cells have developed precise and well regulated mechanisms to control progression through the cell cycle
Flow cytometry profiles of wild type and junBϪ/Ϫ 3T3 cells taken at distinct time points throughout the cell cycle revealed an accelerated G1- to S-phase transition in JunB-deficient cells characterized by a higher extent of S-phase cells most prominent 14 h postrelease (Fig. 2, B and C)
We demonstrate that JunB, which so far has been considered to be a negative regulator of AP-1 (46 – 48) and of the G1- to S-transition [32, 33], has an additional, yet unrecognized, positive role in cell cycle regulation
Summary
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 G2/M-phase was diminished This delay in G2/M-transition is caused by impaired cyclin A-CDK2 and cyclin B-CDC2 kinase activities and counteracts the accelerated S-phase entry. CDK activity is controlled by the expression levels of their respective cyclin partners acting as positive coactivators and by negative regulators, the so-called. In addition to the previously described negative function of JunB at the G1- to S-transition our work identifies a novel critical positive role for JunB in cell cycle progression at the S- to G2/M-phase as transcriptional activator of cyclin A and subsequently of the kinase activity of cyclin A-CDK2
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