Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase

Abstract

Response to genotoxic stress can be considered as a multistage process involving initiation of cell-cycle arrest and maintenance of arrest during DNA repair. Although maintenance of G2/M checkpoints is known to involve Chk1, Chk2/Rad53 and upstream components, the mechanisms involved in its initiation are less well defined. Here we report that p38 kinase has a critical role in the initiation of a G2 delay after ultraviolet radiation. Inhibition of p38 blocks the rapid initiation of this checkpoint in both human and murine cells after ultraviolet radiation. In vitro, p38 binds and phosphorylates Cdc25B at serines 309 and 361, and Cdc25C at serine 216; phosphorylation of these residues is required for binding to 14-3-3 proteins. In vivo, inhibition of p38 prevents both phosphorylation of Cdc25B at serine 309 and 14-3-3 binding after ultraviolet radiation, and mutation of this site is sufficient to inhibit the checkpoint initiation. In contrast, in vivo Cdc25C binding to 14-3-3 is not affected by p38 inhibition after ultraviolet radiation. We propose that regulation of Cdc25B phosphorylation by p38 is a critical event for initiating the G2/M checkpoint after ultraviolet radiation.

Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK–mediated activation of the p16Ink4a-p19Arf pathway

“…This result indicates that even after elimination of p16 expression as the primary block to tumor development, secondary mechanisms that contribute to tumor resistance in Ppm1d -/-mice still operated. Thus, Ppm1d deficiency through activation of p38 MAPK could target other molecules that may negatively contribute to proliferation, such as inhibition of Cdc25 phosphatases 9,10,28 or induction of p19. Thus, we propose that p38 MAPK-dependent modulation of cell cycle regulators including expression of the Cdkn2a locus, through inactivation or depletion of Wip1, will be a powerful approach to treating human primary breast cancers as well as other human malignancies.…”

“…In turn, the p38 MAPK pathway has been implicated as a negative regulator of cell cycle progression by several mechanisms, which implies that Wip1 is also an important regulator of cell cycle progression. p38 MAP kinase inhibits expression of D-type cyclins at transcriptional and post-translational levels 7,8 , phosphorylates and induces degradation of the Cdc25A phosphatase 9 , inhibits the Cdc25B phosphatase through phosphorylation of 14-3-3 sites 10 and phosphorylates the p53 tumor suppressor on two activating sites (Ser33 and Ser46) in the N-terminal region, which contribute to p53-mediated apoptosis 2,11 . Together, these p38 MAPK targets cooperate to activate cell cycle checkpoints, which implies that defects in p38 MAPK regulation or function may perturb cell cycle progression leading to increased tumorigenesis.…”

The tumor suppressor activity of SOCS-1

“…A recent study showed that SOCS-1 increased and sustained the activation of p38 HOG in response to TNFa in murine ®broblasts, a response that was impaired in SOCS-1 de®cient cells (Morita et al, 2000). Although the pathway by which SOCS-1 couples to p38 HOG is unknown, activation of p38 HOG may be one mechanism of how SOCS-1 arrests cells transiting the cell cycle (Alderton et al, 2001;Bulavin et al, 2001).…”

The decatenation checkpoint

“…It is possible that p38 signalling is common to several G 2 /M checkpoints that are distinguished by other signalling events. One study proposed that p38 is an 'early sensor' for cell damage, although only for certain types of stress or damage (Bulavin et al, 2001). The antephase checkpoint was proposed to be independent of ATM and the DNA damage checkpoint yet was induced by treatments that produced large quantities of DSBs (Mikhailov et al, 2004); if the damage and antephase checkpoints were independent, then the damage checkpoint impairment in A-T cells (with mutation in ATM) would be masked by the p38-mediated response, but A-T cells consistently exhibit a checkpoint defect.…”