Cdc25 Inhibited In Vivo and In Vitro by Checkpoint Kinases Cds1 and Chk1

Furnari, Beth; Blasina, Alessandra; Boddy, Michael N.; McGowan, Clare H.; Russell, Paul

doi:10.1091/mbc.10.4.833

Cited by 203 publications

(179 citation statements)

References 48 publications

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“…Thus, activation of ATM leads to CHK2 activation through phosphorylation at Thr68, which in turn phosphorylates CDC25C at Ser216 to block its function (Matsuoka et al, 1998a;Lopez-Girona et al, 2001). The inhibition is mediated by binding of the phosphorylated form of CDC25C to the 14-3-3 protein that is thought to render CDC25C catalytically less active and to cause its sequestration in the cytoplasm Blasina et al, 1999;Furnari et al, 1999;Graves et al, 2000;Lopez-Girona et al, 2001). The relevance of cytoplasmic sequestration of CDC25C remains uncertain, however, as mammalian cells, in contrast to the fission yeast, sequester Cyclin B-CDC2 in the cytoplasm by active export until just before mitosis (see below), and even in the fission yeast forced nuclear localization of CDC25 does not override the G2 arrest (Lopez-Girona et al, 2001;O'Connell et al, 2002).…”

Section: Molecular Mechanisms Of the G2 Checkpointmentioning

confidence: 99%

DNA damage checkpoint control in cells exposed to ionizing radiation

et al. 2003

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Damage induced in the DNA after exposure of cells to ionizing radiation activates checkpoint pathways that inhibit progression of cells through the G1 and G2 phases and induce a transient delay in the progression through S phase. Checkpoints together with repair and apoptosis are integrated in a circuitry that determines the ultimate response of a cell to DNA damage. Checkpoint activation typically requires sensors and mediators of DNA damage, signal transducers and effectors. Here, we review the current state of knowledge regarding mechanisms of checkpoint activation and proteins involved in the different steps of the process. Emphasis is placed on the role of ATM and ATR, as well on CHK1 and CHK2 kinases in checkpoint response. The roles of downstream effectors, such as P53 and the CDC25 family of proteins, are also described, and connections between repair and checkpoint activation are attempted. The role of checkpoints in genomic stability and the potential of improving the treatment of cancer by DNA damage inducing agents through checkpoint abrogation are also briefly outlined.

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Section: Molecular Mechanisms Of the G2 Checkpointmentioning

confidence: 99%

DNA damage checkpoint control in cells exposed to ionizing radiation

et al. 2003

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“…Phosphorylation of CDC25A promotes its degradation through an ubiquitin-mediated mechanism (Mailand et al, 2000;Falck et al, 2001). Phosphorylation of CDC25C on Ser216 inactivates its phosphatase activity either directly (Blasina et al, 1999a;Furnari et al, 1999) or indirectly through the creation of a 14-3-3 binding site (Peng et al, 1997;Sanchez et al, 1997). Finally, CHK1 is believed to shield centrosomal cyclin B1-CDK1 from unscheduled activation during G 2 phase by phosphorylation of CDC25B and creating a 14-3-3 docking site (Giles et al, 2003;Kramer et al, 2004;Schmitt et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Generation of an indestructible cyclin B1 by caspase-6-dependent cleavage during mitotic catastrophe

2008

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Overriding the G 2 DNA damage checkpoint permits precocious entry into mitosis that ultimately leads to mitotic catastrophe. Mitotic catastrophe is manifested by an unscheduled activation of CDK1, caspase activation and apoptotic cell death. We found that although cyclin B1 was required for mitotic catastrophe, it was cleaved into a B35 kDa protein by a caspase-dependent mechanism during the process. Cyclin B1 cleavage occurred after Asp123 in the motif ILVD 123 k, and mutation of this motif attenuated the cleavage. Cleavage was abolished by a pan-caspase inhibitor as well as by specific inhibitors for the effector caspase-6 and the initiator caspase-8. Cleavage created a truncated cyclin B1 lacking part of the NH 2 -terminal regulatory domain that included the destruction box sequence. Although cleavage of cyclin B1 itself was not absolutely required for mitotic catastrophe, expression of the truncated product enhanced cell death. In support of this, ectopic expression of this truncated cyclin B1 was not only sufficient to induce mitotic block and apoptosis but also enhanced mitotic catastrophe induced by ionizing radiation and caffeine. These data underscore a possible linkage between mitotic and apoptotic functions by caspase-dependent processing of mitotic activators.

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“…In cells exposed to Ionizing Radiation, ATM phosphorylates chk2, activating chk2's kinase activity (Blasina et al, 1999a;Brown et al, 1999;Matsuoka et al, 1998). Activated chk2 then phosphorylates the cdc25 tyrosine phosphatase, inhibiting its activity (Blasina et al, 1999b;Furnari et al, 1999). Cyclin B/cdc2 therefore remains inactive, and the cells are arrested in G2 (Blasina et al, 1999b;Furnari et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…Activated chk2 then phosphorylates the cdc25 tyrosine phosphatase, inhibiting its activity (Blasina et al, 1999b;Furnari et al, 1999). Cyclin B/cdc2 therefore remains inactive, and the cells are arrested in G2 (Blasina et al, 1999b;Furnari et al, 1999). If AT cells are irradiated in G2-M, they exhibit a much shorter G2 arrest than normal cells and exit rapidly into G1 Nagasawa et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Activation of p53 transcriptional activity requires ATM's kinase domain and multiple N-terminal serine residues of p53

et al. 2001

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The ATM protein kinase regulates the cell's response to DNA damage by regulating cell cycle checkpoints and DNA repair. ATM phosphorylates several proteins involved in the DNA-damage response, including p53. We have examined the mechanism by which ATM regulates p53's transcriptional activity. Here, we demonstrate that reintroduction of ATM into AT cells restores the activation of p53 by the radio-mimetic agent bleomycin. Further, p53 activation is lost when a kinase inactive ATM is used, or if the N-terminal of ATM is deleted. In addition, AT cells stably expressing ATM showed decreased sensitivity to Ionizing Radiationinduced cell killing, whereas cells expressing kinase inactive ATM or N-terminally deleted ATM were indistinguishable from AT cells. Finally, single pointmutations of serines 15, 20, 33 or 37 did not individually block the ATM-dependent activation of p53 transcriptional activity by bleomycin. However, double mutations of either serines 15 and 20 or serines 33 and 37 blocked the ability of ATM to activate p53. Our results indicate that the N-terminal of ATM and ATM's kinase activity are required for activation of p53's transcriptional activity and restoration of normal sensitivity to DNA damage. In addition, activation of p53 by ATM requires multiple serine residues in p53's transactivation domain. Oncogene (2001) 20, 5100 ± 5110.

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Cdc25 Inhibited In Vivo and In Vitro by Checkpoint Kinases Cds1 and Chk1

Cited by 203 publications

References 48 publications

DNA damage checkpoint control in cells exposed to ionizing radiation

DNA damage checkpoint control in cells exposed to ionizing radiation

Generation of an indestructible cyclin B1 by caspase-6-dependent cleavage during mitotic catastrophe

Activation of p53 transcriptional activity requires ATM's kinase domain and multiple N-terminal serine residues of p53

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