Trends in Cell Biology
Volume 11, Issue 10, 1 October 2001, Pages 426-433
Journal home page for Trends in Cell Biology

Review
Integrating stress-response and cell-cycle checkpoint pathways

https://doi.org/10.1016/S0962-8924(01)02119-5Get rights and content

Abstract

The DNA integrity checkpoint and stress kinase (SAPK/JNK and p38) pathways function to modulate cell-cycle, apoptotic and transcriptional responses to stress. Although initially considered to function independently, recent advances indicate a number of links between the stress-response and checkpoint pathways. Here, we consider the relationship between the stress-response and checkpoint pathways and how they interact to modulate cell-cycle control.

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

References (78)

  • Y. Shiloh

    ATM and ATR: networking cellular responses to DNA damage

    Curr. Opin. Genet. Dev.

    (2001)
  • T. Caspari

    How to activate p53

    Curr. Biol.

    (2000)
  • K.M. Ryan

    Regulation and function of the p53 tumor suppressor protein

    Curr. Opin. Cell Biol.

    (2001)
  • A. Paul

    Stress-activated protein kinases: activation, regulation and function

    Cell. Signal.

    (1997)
  • A.R. Nebreda et al.

    p38 MAP kinases: beyond the stress response

    Trends Biochem. Sci.

    (2000)
  • K. Mielke et al.

    JNK and p38 stress kinases – degenerative effectors of signal transduction-cascades in the nervous system

    Prog. Neurobiol.

    (2000)
  • O. Potapova

    c-Jun N-terminal kinase is essential for growth of human T98G glioblastoma cells

    J. Biol. Chem.

    (2000)
  • M.H. Green

    Hypersensitivity of ataxia telangiectasia fibroblasts to a nitric oxide donor

    Free Radic. Biol. Med.

    (1997)
  • D. Watters

    Localization of a portion of extranuclear ATM to peroxisomes

    J. Biol. Chem.

    (1999)
  • R.E. Shackelford

    The Ataxia telangiectasia gene product is required for oxidative stress-induced G1 and G2 checkpoint function in human fibroblasts

    J. Biol. Chem.

    (2001)
  • J.A. Flattery-O'Brien et al.

    Hydrogen peroxide causes Rad9-dependent cell cycle arrest in G2 in Saccharomyces cerevisiae whereas menadione causes G1 arrest independent of Rad9 function

    J. Biol. Chem.

    (1998)
  • F. Posas

    The transcriptional response of yeast to saline stress

    J. Biol. Chem.

    (2000)
  • C. Godon

    The H2O2 stimulon in Saccharomyces cerevisiae

    J. Biol. Chem.

    (1998)
  • K. Vido

    A proteome analysis of the cadmium response in Saccharomyces cerevisiae

    J. Biol. Chem.

    (2001)
  • B.B. Zhou et al.

    The DNA damage response: putting checkpoints in perspective

    Nature

    (2000)
  • M. Shimada

    Replication factor C3 of Schizosaccharomyces pombe, a small subunit of replication factor C complex, plays a role in both replication and damage checkpoints

    Mol. Biol. Cell

    (1999)
  • N. Rhind et al.

    Chk1 and Cds1: linchpins of the DNA damage and replication checkpoint pathways

    J. Cell Sci.

    (2000)
  • S. Bao

    ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses

    Nature

    (2001)
  • B. Vogelstein

    Surfing the p53 network

    Nature

    (2000)
  • W.R. Taylor et al.

    Regulation of the G2/M transition by p53

    Oncogene

    (2001)
  • J.B. Millar

    Stress-activated MAP kinase (mitogen-activated protein kinase) pathways of budding and fission yeasts

    Biochem. Soc. Symp.

    (1999)
  • J.R. Woodgett

    The stress activated protein kinase pathway

    Cancer Surv.

    (1996)
  • L.A. Tibbles et al.

    The stress-activated protein kinase pathways

    Cell Mol. Life Sci.

    (1999)
  • V. Buck

    Peroxide sensors for the fission yeast stress-activated mitogen-activated protein kinase pathway

    Mol. Biol. Cell

    (2001)
  • A.N. Nguyen

    Multistep phosphorelay proteins transmit oxidative stress signals to the fission yeast stress-activated protein kinase

    Mol. Biol. Cell

    (2000)
  • S. Gupta

    Selective interaction of JNK protein kinase isoforms with transcription factors

    EMBO J.

    (1996)
  • C. Widmann

    Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human

    Physiol. Rev.

    (1999)
  • B. Derijard

    Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms

    Science

    (1995)
  • L. Molz

    Cdc2 and the regulation of mitosis: six interacting mcs genes

    Genetics

    (1989)
  • Cited by (146)

    • HDAC inhibition in cancer

      2022, Epigenetics in Organ Specific Disorders
    • Cell-cycle involvement in autophagy and apoptosis in yeast

      2017, Mechanisms of Ageing and Development
    View all citing articles on Scopus
    View full text