A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase

Blasina, Alessandra; Weyer, Inez Van de; Laus, Marc C.; Luyten, Walter; Parker, Andrew E.; McGowan, Clare H.

doi:10.1016/s0960-9822(99)80041-4

Cited by 258 publications

(230 citation statements)

References 50 publications

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“…In keeping with a defect in the G2 delay, A-T cells do not exhibit a reduction in the activities of the Cdc2 kinase and the Cdc25C phosphatase, shortly after irradiation (Paules et al, 1995;Beamish et al, 1996;Blasina et al, 1999). Accordingly, the rapid modi®cation and activation of Chk2 in response to IR and other DSBs generating agents, but not to UV or HU, is also dependent on ATM (Matsuoka et al, 1998;Brown et al, 1999;Chaturvedi et al, 1999;Uziel, unpublished).…”

Section: G2/m Checkpointmentioning

confidence: 98%

“…Inactivation of Cdc25C is mediated by two protein kinases, Chk1 and Chk2 (HuCds1), which are phosphorylated and activated in response to DNA damage. Chk2 also responds to replication blocks such as those caused by treatment with hydroxyurea (HU) (Sanchez et al, 1997;Matsuoka et al, 1998;Blasina et al, 1999;Brown et al, 1999;Chaturvedi et al, 1999).…”

Section: G2/m Checkpointmentioning

confidence: 99%

“…Blasina et al (1999) reported that both these kinases directly phosphorylate and inactivate Cdc25C in vitro. However, an alternative explanation suggests that in vivo phosphorylation of Cdc25C on Ser-216, the site phosphorylated by Chk1 and Chk2 in vitro (Sanchez et al, 1997;Matsuoka et al, 1998;Brown et al, 1999), promotes Cdc25C binding to 14-3-3 proteins, leading to its export from the nucleus and sequestration in the cytoplasm.…”

Section: G2/m Checkpointmentioning

confidence: 99%

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ATM: A mediator of multiple responses to genotoxic stress

1999

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The ATM protein kinase is the product of the gene responsible for the pleiotropic recessive disorder ataxiatelangiectasia. ATM-de®cient cells show enhanced sensitivity and greatly reduced responses to genotoxic agents that generate DNA double strand breaks (DSBs), such as ionizing radiation and radiomimetic chemicals, but exhibit normal responses to DNA adducts and base modi®cations induced by other agents. Therefore, DSBs are most likely the predominant signal for the activation of ATM-mediated pathways. Identi®cation of the ATM gene triggered extensive research aimed at elucidating the numerous functions of its large multifaceted protein product. While ATM has both nuclear and cytoplasmic functions, this review will focus on its roles in the nucleus where it plays a central role in the very early stages of damage detection and serves as a master controller of cellular responses to DSBs. By activating key regulators of multiple signal transduction pathways, ATM mediates the e cient induction of a signaling network responsible for repair of the damage, and for cellular recovery and survival.

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Section: G2/m Checkpointmentioning

confidence: 98%

Section: G2/m Checkpointmentioning

confidence: 99%

Section: G2/m Checkpointmentioning

confidence: 99%

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ATM: A mediator of multiple responses to genotoxic stress

1999

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“…[1][2][3][4][5][6][7][8] Upon DNA damage, Chk2 is activated by phosphorylation of threonine68 (Thr68) by ATM (ataxiatelangiectasia mutated). [9][10][11][12][13] Activated Chk2 then phosphorylates its downstream effectors, including the tumour suppressors p53, BRCA1, PML, E2F-1, and Cdc25 phosphatases, [14][15][16][17][18][19] thereby regulating cellular responses following DNA damage. Although the molecular basis of Chk2 kinase activation and roles of Chk2 in checkpoint activation are rather well understood, it remains largely unknown as to how activated Chk2 is inhibited to release from checkpoint arrest or to prevent cells from undergoing Chk2-mediated apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase

et al. 2005

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The antioncogenic Chk2 kinase plays a crucial role in DNA damage-induced cell-cycle checkpoint regulation. Here we show that Chk2 associates with the oncogenic protein Wip1 (wild-type p53-inducible phosphatase 1) (PPM1D), a p53-inducible protein phosphatase. Phosphorylation of Chk2 at threonine68 (Thr68), a critical event for Chk2 activation, which is normally induced by DNA damage or overexpression of Chk2, is inhibited by expression of wild-type (WT), but not a phosphatase-deficient mutant (D314A) of Wip1 in cultured cells. Furthermore, an in vitro phosphatase assay revealed that Wip1 (WT), but not Wip1 (D314A), dephosphorylates Thr68 on phosphorylated Chk2 in vitro, resulting in the inhibition of Chk2 kinase activity toward glutathione S-transferase-Cdc25C. Moreover, inhibition of Wip1 expression by RNA interference results in abnormally sustained Thr68 phosphorylation of Chk2 and increased susceptibility of cells in response to DNA damage, indicating that Wip1 acts as a negative regulator of Chk2 in response to DNA damage.

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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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A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase

Abstract: These results suggest that, in human cells, the DNA-damage checkpoint involves direct inactivation of Cdc25 catalyzed by Cds1 and/or Chk1.

Cited by 258 publications

References 50 publications

ATM: A mediator of multiple responses to genotoxic stress

ATM: A mediator of multiple responses to genotoxic stress

Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase

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

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