Trends in Cell Biology
ReviewIntegrating stress-response and cell-cycle checkpoint pathways
Section snippets
Cell-cycle checkpoint pathways
Checkpoint pathways function to ensure that initiation of late cell-cycle events is dependent upon the completion of earlier ones. Two such pathways have been characterized in detail and are highly conserved. The spindle assembly checkpoint functions to delay mitosis until the mitotic spindle is correctly formed. Disruption of the mitotic spindle results in cell-cycle arrest through activation of this checkpoint 1, 2, 3. DNA-integrity checkpoints function to delay the cell cycle in response to
Stress-activated MAP kinase pathways
Mitogen-activated protein kinase (MAPK) pathways transmit environmental signals from the cell membrane to the nucleus through phosphorylation cascades, resulting in the activation of transcription factors, which in turn regulate gene expression. The core components of these pathways are conserved in all eukaryotic systems (Fig. 2). This core consists of a kinase cascade in which a MAPKKK phosphorylates a MAPKK, which in turn phosphorylates a MAPK. In mammalian systems, there are three subgroups
A role for stress kinases in cell-cycle modulation
A role for stress-response pathways in cell-cycle control has been well documented in fission yeast, where disruption of components of the Spc1/Sty1 pathway leads to an extended G2 phase, and conversely activation of the pathway results in a shortened G2 period (summarized in Table 2). In budding yeast, the cellular response to osmotic stress is regulated by the stress kinase Hog1. Recent evidence indicates that Hog1, together with the kinase Swe1, regulates a G2 delay resulting from exposure
A role for stress kinases in DNA-damage checkpoints
In addition to the role of stress-response pathways in cell-cycle control and spindle cell-cycle checkpoints, there have been a number of recent advances indicating that the stress-response and DNA-integrity checkpoint pathways might be intricately linked in coordinating responses to DNA damage. A role for p38 in the checkpoint governing the G2–M transition was recently demonstrated by Wang et al.47 in mammalian cells. These authors demonstrated that a MAPKK–p38γ cascade is required for a
A role for DNA-integrity checkpoints in the response to oxidative stress
Available evidence indicates that the stress kinase pathways perform a primary role in the cellular response to oxidative stress. However, as oxidative stress is the principal source of DNA lesions in aerobic organisms, a role for DNA-integrity checkpoint pathways in the cellular response to oxidative stress might be predicted. Significant evidence in support of a role for checkpoint proteins in the cellular response to oxidative stress has come from studies into the disease
Conclusions and future perspectives
The findings described here provide evidence for considerable functional overlap between stress-response and checkpoint pathways in cell-cycle control. These findings establish a role for stress kinase pathways in spindle checkpoints and DNA-integrity checkpoints. Moreover, roles for DNA-integrity checkpoints in oxidative stress responses have also been determined. Stress kinase and checkpoint pathways therefore function coordinately to provide an integrated cell-cycle response to genotoxic
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