Cyclin B1 proteolysis via p38 MAPK signaling participates in G2 checkpoint elicited by arsenite

Timely induction of cyclin B1 controls mitotic entry, whereas its proteolysis is essential for mitotic exit. By contrast, cyclin B1 transcription is repressed during G2 arrest induced by DNA damage. The p38 mitogen-activated protein kinase is involved in the G2 checkpoint; yet, its impact on cyclin B1 protein levels remains unclear. Here we show that untimely proteolysis of cyclin B1 following p38 activation contributes to G 2 checkpoint. Exposing early G2 cells to arsenite impeded cyclin B1 protein accumulation, Cdk1 activation, and G2-to-M progression. Conversely, cyclin B1 was non-degradable in late G2 and mitotic cells after arsenite. Cyclin B1 proteolysis was enhanced by arsenite in early G2 and asynchronous cells. This rapid destruction of cyclin B1 was mediated via the ubiquitin-proteasome pathway probably in a Cdc20 and Cdh1 independent mechanism. Under arsenite, inhibition of p38 activation or depletion of p38α suppressed cyclin B1 ubiquitination and proteolysis, while forced expression of MKK6-p38 accelerated these events. Inactivation of p38 in arsenite-treated early G2 cells allowed G2-to-M progression, blocked apoptosis, increased cell viability, and decreased micronucleus formation. Thus, p38 signaling pathway triggering cyclin B1 proteolysis after arsenite may play an important role in connecting G 2 arrest with apoptosis or genome instability.