The <i>Xenopus</i> Chk1 Protein Kinase Mediates a Caffeine-sensitive Pathway of Checkpoint Control in Cell-free Extracts

Kumagai, Akiko; Guo, Zijian; Emami, Katayoon H.; Wang, Sophie X.; Dunphy, William G.

doi:10.1083/jcb.142.6.1559

Cited by 232 publications

(286 citation statements)

References 52 publications

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“…Furthermore, caffeine, an agent capable of antagonizing As 2 O 3 -induced G 2 /M arrest, also blocked As 2 O 3 -induced Dj m collapse and apoptosis. Based on these observations as well as those reported by others, 21,22 we propose that mitotic arrest is a common mechanism for As 2 O 3 -induced apoptosis in most cancer cells. …”

Section: Discussionmentioning

confidence: 85%

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Arsenic trioxide-induced mitotic arrest and apoptosis in acute promyelocytic leukemia cells

Huang

et al. 2003

Leukemia

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Arsenic trioxide (As 2 O 3 ), an effective drug for the treatment of acute promyelocytic leukemia (APL), can induce apoptosis and partial differentiation in APL cells in vitro and in vivo. However, As 2 O 3 also induces apoptosis in cancer cells other than APL with complex mechanisms, which seem to be cell type dependent. In this study, we report that APL cells (NB4 cell line) are arrested at early mitotic phase before the collapse of mitochondrial transmembrane potential (Du m ) and apoptosis after treatment with pharmacological concentrations (1.0-2.0 lM) of As 2 O 3 . We have also made the following new discoveries: (1) 0.5 lM As 2 O 3 that fails to induce apoptosis has no effects on cell cycle distribution. (2) With inhibition of As 2 O 3 -induced Du m collapse and apoptosis, dithiothreitol also effectively inhibits As 2 O 3 -induced mitotic arrest, suggesting that both As 2 O 3 -induced apoptosis and mitotic arrest involve proteins with thiol groups. (3) 1.5 mM caffeine that relieves cells from G 2 /M arrest also inhibits As 2 O 3 -induced Du m collapse and apoptosis, (4) 1.0 lM As 2 O 3 increases the expression of both cyclin B 1 and hCDC20 whereas it inhibits Tyr15 phosphorylation of p34 cdc2 . In conclusion, our results strongly support that there is a tight link between As 2 O 3 -induced apoptosis and mitotic arrest, the latter being one of common mechanisms for As 2 O 3 -induced apoptosis in cancer cells.

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Section: Discussionmentioning

confidence: 85%

“…Although caffeine has multiple effects on cell physiology, it was widely used to specifically relieve cells from early mitotic arrest. 22 Cyclin B1 and hCDC20 were upregulated while Tyr15 phosphorylation of p34 cdc2 was decreased upon treatment with 1.0 mM As 2 O 3…”

Section: Dtt Inhibited As 2 O 3 -Induced Mitotic Arrest In Nb4 Cellsmentioning

confidence: 99%

Arsenic trioxide-induced mitotic arrest and apoptosis in acute promyelocytic leukemia cells

Huang

et al. 2003

Leukemia

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“…How ca eine is able to disrupt these checkpoint pathways is not yet fully understood but recent observations on Xenopus eggs suggest that ca eine could abolish the phosphorylation of Chk1, thus preventing the phosphorylation of Cdc25C on Ser-287 residue. The lack of phosphorylation of Cdc25C prevents its sequestration by 14 ± 3 ± 3 proteins, thus allowing the activation of CDK1 (Kumagai et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

The bacterial cytolethal distending toxin (CDT) triggers a G2 cell cycle checkpoint in mammalian cells without preliminary induction of DNA strand breaks

et al. 1999

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The bacterial cytolethal distending toxin (CDT) was previously shown to arrest the tumor-derived HeLa cell line in the G2-phase of the cell cycle through inactivation of CDK1, a cyclin-dependent kinase whose state of activation determines entry into mitosis. We have analysed the e ects induced in HeLa cells by CDT, in comparison to those induced by etoposide, a prototype anti-tumoral agent that triggers a G2 cell cycle checkpoint by inducing DNA damage. Both CDT and etoposide inhibit cell proliferation and induces the formation of enlarged mononucleated cells blocked in G2. In both cases, CDK1 from arrested cells could be reactivated both in vitro by dephosphorylation by recombinant Cdc25B phosphatase and in vivo by ca eine. However, the cell cycle arrest triggered by CDT, unlike etoposide, did not originate from DNA strand breaks as demonstrated in the single cell gel electrophoresis assay and by the absence of slowing down of S phase in synchronized cells. Together with additional observations on synchronized HeLa cells, our results suggest that CDT triggers a G2 cell cycle checkpoint that is initiated during DNA replication and that is independent of DNA damage.

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“…Studies with Xenopus egg extracts have demonstrated that the Chk1 pathway inhibits entry into mitosis in the presence of unreplicated or UVirradiated DNA (Kumagai et al, 1998a). The simplest explanation of the phenotype is that geminin deficiency causes a subtle defect in DNA structure that activates the pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Chk1 prevents Cdc2 dephosphorylation by negatively regulating Cdc25C, the phosphatase that removes the inhibitory phosphates from Cdc2. Chk1 phosphorylates Cdc25C on serine-287 (S287), generating a binding site for a member of the 14-3-3 family of proteins (Peng et al, 1997;Kumagai et al, 1998a;Kumagai and Dunphy, 1999). 14-3-3 binding masks a nuclear localization signal on Cdc25C and causes the phosphatase to be retained in the cytoplasm, where it presumably cannot dephosphorylate nuclear Cdc2.…”

Section: Bypassing Chk1 Pathway Suppresses G2 Arrest Caused By Geminimentioning

confidence: 99%

Geminin Deficiency Causes a Chk1-dependent G2 Arrest inXenopus

McGarry

2002

MBoC

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Geminin is an unstable inhibitor of DNA replication that gets destroyed at the metaphase/ anaphase transition. The biological function of geminin has been difficult to determine because it is not homologous to a characterized protein and has pleiotropic effects when overexpressed. Geminin is thought to prevent a second round of initiation during S or G2 phase. In some assays, geminin induces uncommitted embryonic cells to differentiate as neurons. In this study, geminin was eliminated from developing Xenopus embryos by using antisense techniques. Geminindeficient embryos show a novel and unusual phenotype: they complete the early cleavage divisions normally but arrest in G2 phase immediately after the midblastula transition. The arrest requires Chk1, the effector kinase of the DNA replication/DNA damage checkpoint pathway. The results indicate that geminin has an essential function and that loss of this function prevents entry into mitosis by a Chk1-dependent mechanism. Geminin may be required to maintain the structural integrity of the genome or it may directly down-regulate Chk1 activity. The data also show that during the embryonic cell cycles, rereplication is almost entirely prevented by gemininindependent mechanisms.

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The Xenopus Chk1 Protein Kinase Mediates a Caffeine-sensitive Pathway of Checkpoint Control in Cell-free Extracts

Cited by 232 publications

References 52 publications

Arsenic trioxide-induced mitotic arrest and apoptosis in acute promyelocytic leukemia cells

Arsenic trioxide-induced mitotic arrest and apoptosis in acute promyelocytic leukemia cells

The bacterial cytolethal distending toxin (CDT) triggers a G2 cell cycle checkpoint in mammalian cells without preliminary induction of DNA strand breaks

Geminin Deficiency Causes a Chk1-dependent G2 Arrest inXenopus

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