MAPKAP Kinase-2 Is a Cell Cycle Checkpoint Kinase that Regulates the G2/M Transition and S Phase Progression in Response to UV Irradiation

Manke, Isaac A.; Nguyen, Anhco; Lim, Daniel; Stewart, Mary Q.; Elia, Andrew E. H.; Yaffe, Michael B.

doi:10.1016/j.molcel.2004.11.021

Cited by 382 publications

(410 citation statements)

References 56 publications

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“…6 Biochemically, CDC2 has also been identified as a downstream target for the p38-MAPK pathway. 13 We therefore speculated that a molecular antagonism between these two different stresssignaling pathways might converge on CDC2. Since mkk7-deficient MEFs show reduced CDC2 expression and impaired CyclinB1 associated CDC2 kinase activity depending on the cell passage, 6 we examined whether CyclinB1 associated CDC2 kinase activity can be rescued by inhibition of the p38-MAPK pathway.…”

Section: Resultsmentioning

confidence: 99%

Antagonistic control of cell fates by JNK and p38-MAPK signaling

et al. 2007

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Section: Resultsmentioning

confidence: 99%

Antagonistic control of cell fates by JNK and p38-MAPK signaling

et al. 2007

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“…CDC25B phosphatase activity appears to be highly regulated by phosphorylation mechanisms. A number of regulatory kinases that activate or inhibit CDC25B have been identified (Baldin et al, 1997a(Baldin et al, , 2003Bulavin et al, 2002;Theis-Febvre et al, 2003;Dutertre et al, 2004;Cazales et al 2005;Manke et al, 2005;Mirey et al, 2005;Lemaire et al, 2006;Schmitt et al, 2006) (our unpublished data). These phosphorylation events modulate the catalytic activity, the interactions with regulatory partners such as 14-3-3 proteins, the localization and probably also the stability of CDC25B.…”

Section: Introductionmentioning

confidence: 90%

Differential mitotic degradation of the CDC25B phosphatase variants

et al. 2007

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CDC25 phosphatases control cell-cycle progression by dephosphorylating and activating cyclin-dependent kinases. CDC25B, one of the three members of this family in human cells, is thought to regulate initial mitotic events. CDC25B is an unstable protein whose proteasomal degradation is proposed to be controlled by b-TrCP. Here, we have investigated the regulation of CDC25B during mitosis, using time-lapse video microscopy. We found that CDC25B expression is high during early mitosis, and that its degradation occurs after the metaphase-anaphase transition and cyclin B1 destruction. We also show that CDC25B degradation after metaphase is dependent on the integrity of the KEN-box and RRKSE motifs that are located within the alternatively spliced B domain, and that the CDC25B2 splice variant, that lacks this domain, is stable during mitosis. Furthermore, we show that the N-terminal region of CDC25B, encompassing the B domain, undergoes major conformational changes during mitosis that can be monitored by intramolecular fluorescence resonance energy transfer variation of specific CDC25B biosensors. This study demonstrates that CDC25B splice variants have differential mitotic stabilities, a feature that is likely to have major consequences on the local control of cyclin-dependent kinase-cyclin activities during mitotic progression.

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“…At G2, Chk1 is activated by ATR to phosphorylate CDC25A, -B, and -C (Boutros, 2006), preventing cyclin B/CDK1 activation and resulting in G2 arrest. Another mechanism of G2 arrest is provided by stress-induced activation of p38 MAPK/MK2 and subsequent inactivation of CDC25B/C, as described earlier (Manke et al, 2005;Reinhardt et al, 2007). By inducing the transcription of p21 and other proteins, p53 also plays a role in the G2 checkpoint (Taylor and Stark, 2001).…”

Section: G2 Checkpointmentioning

confidence: 97%

“…Another transducer kinase, downstream from the stressresponse p38 MAPK pathway and named MAPKAP kinase-2 (MK2), is directly involved in phosphorylating effectors CDC25B and C, and in maintaining G1, S, and G2 checkpoints triggered by UV-induced DNA damage (Manke et al, 2005). MAPKAP kinase-2 is activated by cisplatin, camptothecin, and doxorubicin, and the MK2 response is essential for the survival of p53-deficient cells following exposure to these agents (Reinhardt et al, 2007).…”

Section: Molecular Components Of the Dna Damage Checkpointsmentioning

confidence: 99%

“…More recently, this pathway has been found to be a regulator of checkpoint controls, particularly at the G2/M transition (Manke et al, 2005). MK2-depleted p53-deficient cells cause not only abrogation of the CDC25A-mediated S-phase checkpoint after cisplatin treatment, but also loss of the CDC25B-mediated G2/M checkpoint following doxorubicin (Reinhardt et al, 2007).…”

Section: Mk2 Inhibitionmentioning

confidence: 99%

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G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer

2008

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Rigorous quality control steps, termed checkpoints, tightly regulate progression through the cell cycle. DNA-damaging chemotherapy and radiation activate functional cellular checkpoints. These checkpoints can facilitate DNA repair and promote cell death in unrepaired cells. There are at least three DNA damage checkpoints -at G1/S, S, and G2/M -as well as a mitotic spindle checkpoint. Most cancer cells harbour mutations in tumour suppressors and/or oncogenes, which impair certain cell checkpoints. Inhibiting the remaining cell checkpoints -particularly after exposure of cancer cells to chemotherapy and/or radiation -allows cell death, a strategy now being employed in cancer therapeutics. With our increasing knowledge of cell cycle regulation, many compounds have been developed to inhibit specific checkpoint components, particularly at the G2/M transition. One such target is checkpoint kinase-1 (Chk1). We review here the molecular framework of the cell cycle, the rationale for targeting Chk1, the preclinical concepts related to the development of Chk1 inhibitors, and the efficacy and safety results from Chk1 inhibitors now in phase I/II trials. British Journal of Cancer (2008) The cell cycle is organised into a series of dependent pathways, whereby the initiation of each event is dependent upon successful completion of previous events. In this way, replicating cells traverse the four distinct phases of the cell cycle consecutively: G1 followed by S, followed by G2 and, finally, M. This ordered progression is guarded by checkpoints capable of delaying the cell cycle in response to intra-or extracellular stressors. As part of the cell cycle surveillance system, the DNA damage and spindle checkpoints protect the cell from genomic instability. Checkpoints are important quality control measures that ensure the proper sequence of cell cycle events and allow cells to respond to DNA damage.Increasingly, checkpoint inhibition has become an area of novel drug development. In the setting of DNA damage, checkpoint inhibition leads to genomic instability, and subsequent cell death. The first checkpoint, found at the G1/S transition, is compromised in many malignant cells, due to mutations in various tumour suppressor genes, including retinoblastoma protein (Rb) and p53. Cells deficient in the G1 checkpoint are dependent on the S and G2 checkpoints for DNA repair. Checkpoint kinase-1 (Chk1) is an active transducer kinase at both the S and G2 checkpoints, rendering it a target for rational anticancer drug development. In the presence of DNA damage, Chk1 inactivation abrogates G2 arrest, resulting in preferential cancer cell death .This article serves to review the (1) current molecular pathways comprising the cell cycle checkpoint machinery, (2) inhibition of Chk1 as an effective means of abrogating G2 arrest, and (3) current Chk1 inhibitors in use in phase I clinical trials.

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MAPKAP Kinase-2 Is a Cell Cycle Checkpoint Kinase that Regulates the G2/M Transition and S Phase Progression in Response to UV Irradiation

Cited by 382 publications

References 56 publications

Antagonistic control of cell fates by JNK and p38-MAPK signaling

Antagonistic control of cell fates by JNK and p38-MAPK signaling

Differential mitotic degradation of the CDC25B phosphatase variants

G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer

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