Active MAP Kinase in Mitosis: Localization at Kinetochores and Association with the Motor Protein CENP-E

Zečević, Maja; Catling, Andrew D.; Eblen, Scott T.; Renzi, L.; Hittle, James C.; Yen, Tim J.; Gorbsky, Gary J.; Weber, Michael J.

doi:10.1083/jcb.142.6.1547

Cited by 206 publications

(208 citation statements)

References 63 publications

(98 reference statements)

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“…For example, activation of the MEK/ERK pathway is required for exit from DNA damage-induced G2 cell cycle arrest (Abbott and Holt, 1999) and the transition from G2 into M (Lavoie et al, 1996;Wright et al, 1999). In addition, the localisation of active ERK to the mitotic kinetochore is also suggested to regulate proteins involved in chromosome segregation during metaphase to anaphase transition (Shapiro et al, 1998;Zecevic et al, 1998). Furthermore, ERK is also described to associate with kinetochores during early prophase, but this association is not apparent at later stages of mitosis (Knauf et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Role of MEK/ERK pathway in the MAD2-mediated cisplatin sensitivity in testicular germ cell tumour cells

et al. 2006

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Testicular germ cell tumour (TGCT) is the most common malignancy in young males. Although most TGCTs are sensitive to cisplatin-based chemotherapy, significant numbers of TGCT patients still relapse and die each year because of the development of resistance to cisplatin. Previously, we first reported that a key regulator of the mitotic checkpoint, mitotic arrest deficient-2 (MAD2), was a mediator of cisplatin sensitivity in human cancer cells. In this study, we investigated whether MAD2 played a role in cellular sensitivity to cisplatin in TGCT cells and the underlying molecular mechanisms responsible. Using 10 TGCT cell lines, we found that increased MAD2 expression was correlated with cellular sensitivity to cisplatin, which was associated with activation of the MEK pathway. Treatment of cells expressing high levels of MAD2 with an MEK inhibitor, U0126, led to cellular protection against cisplatininduced apoptosis. Inactivation of MAD2 by transfecting a dominant-negative construct in TGCT cells with high levels of MAD2 resulted in the suppression of MEK pathway and resistance to cisplatin-induced cell death. These results support previous suggestion on the involvement of mitotic checkpoint in DNA damage response in human cancer cells and demonstrate a possible molecular mechanism responsible for the MAD2-mediated sensitivity to cisplatin in TGCT cells. Our results also suggest that downregulation of MAD2 may be an indicator for identification of TGCT cancer cells that are potentially resistant to cisplatin-based therapy.

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Section: Discussionmentioning

confidence: 99%

Role of MEK/ERK pathway in the MAD2-mediated cisplatin sensitivity in testicular germ cell tumour cells

et al. 2006

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“…MEK1 has been shown to interact with spindle checkpoint proteins, 23 and the activity of MEK1 is reduced upon anaphase entry. 24 If LY-294002-induced cell death was dependent on the ability of cells to leave metaphase, MEK1 inhibition might have conferred an additional signal to LY-294002-treated H157 cells to leave metaphase, while upon PKC 412 treatment escape from metaphase was potently inhibited and therefore the decrease in the MEK1 signal had no effect. Interestingly, MEK inhibition also sensitizes H157 cells to death induced by the microtubule stabilizing drug paclitaxel that blocks cell cycle progression in mitosis.…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of the PI3‐kinase/Akt pathway induce mitotic catastrophe in non‐small cell lung cancer cells

Hemström

Sandström

Zhivotovsky

2006

Intl Journal of Cancer

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Non-small cell lung cancer cells (NSCLC) are more resistant to anticancer treatment as compared with other types of cancer cells. Recently (Hemstr€ om et al., Exp Cell Res 2005;305:200-13) we showed that apoptosis of U1810 NSCLC cells induced by the staurosporine analog PKC 412 correlated with inhibition of Akt and ERK1/2, suggesting the involvement of these kinases in cell survival. Here we investigated the contribution of the PI3-kinase/Akt and MEK/ERK pathways to survival of NSCLC cells. The two signaling pathways were studied by using different combinations of the PI3-kinase inhibitors LY-294002 and wortmannin, the Akt activator Ro 31-8220, the MEK inhibitor PD 98059 and PKC 412. PI3-kinase inhibitors induced apoptosis-like death in U1810 cells. H157 cells in general were relatively resistant to PI3 kinase/Akt inhibitors yet these compounds sensitized cells to the DNA-damaging drug VP-16, while Ro 31-8220 could not. PD 98059 only had a sensitizing effect on H157 cells when combined with PI3-kinase inhibition and VP-16. Key words: mitotic catastrophe; non-small cell lung carcinoma; PI3-kinase; Akt; apoptosis Cell lines derived from non-small cell lung carcinoma (NSCLC) are most often characterized by cellular resistance towards anticancer drugs and radiation. 1 Efficiency of action of DNA-damaging drugs used in anticancer therapy depends on the successful ability to induce growth arrest and to activate the cell death machinery. 2 Apoptosis induced by DNA damage is typically associated with activation of a family of proteases, the caspases, as a result of a sequence of mitochondria-mediated events. The caspases cleave many proteins, eventually leading to biochemical and morphological apoptosis-specific changes. In addition to activation of the caspases, mediated by release of cytochrome c, several proteins, such as apoptosis inducing factor (AIF) and endonuclease G are also released from mitochondria, translocate to the nuclei and induce chromatin condensation and cell death independently of caspases.Cell cycle regulation is also an important determinant for efficiency of cell death in response to DNA damage. For example, topoisomerase inhibitors are suggested to be particularly effective in S-phase when DNA replication occurs, 3 while irradiated cells are most sensitive at G2/M phase. 4 DNA-damaged cells are removed by cell death following activation of the DNA damage checkpoints in G1 and G2-phases of the cell cycle. 5 There are many mechanisms for cells being resistant to DNA damage. 6 For example, resistant lung cancer cells have an increased activity of DNAdependent protein kinase (DNA-PK) and DNA repair, correlating with a decreased incidence of cell death, suggesting involvement of DNA-PK in tumor survival. 7,8 Aberrant signaling of other kinases, such as the Ras/MEK/ERK and PI3-kinase/Akt pathways is also contributes to cell death resistance. In NSCLC-patients phospho-Akt overexpression confers a stage-independent survival disadvantage 9 and in NSCLC cell lines a high activity of Akt promotes cellular...

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“…Besides motor enzymes, a number of other proteins are at least transiently associated with kinetochores during mitosis. These include rod (Karess and Glover 1989; Starr et al, 1998), the MAP kinases ppERK (Shapiro et al 1998; Zecevic et al 1998) and ppMEK (Shapiro et al 1998), and an APC activator protein fizzy (called cdc20/cdh1 in other organisms; Kallio et al 1998). Likewise, the protein kinase polo (Logarinho and Sunkel 1998) and a number of components of the highly conserved spindle assembly checkpoint, including Bub1 (Taylor and McKeon 1997; Taylor et al 1998; Basu et al 1999), Bub3 (Taylor et al 1998; Basu et al 1998; Martinez-Exposito et al 1999), Mad1 (Jin et al 1998; Chen et al 1998), and Mad2 (Waters et al 1998; Chen et al 1996, Chen et al 1998), are transiently kinetochore-bound.…”

Section: Introductionmentioning

confidence: 99%

“…Wood, and D.W. Cleveland, manuscript submitted for publication). CENP-E is also a target of phosphorylation by the map kinase ppERK, an active kinase found at the kinetochore (Shapiro et al 1998; Zecevic et al 1998). CENP-E has also been implicated in the dynamic attachment of kinetochores to disassembling microtubules in vitro (Lombillo et al 1995).…”

Section: Introductionmentioning

confidence: 99%

CENP-meta, an Essential Kinetochore Kinesin Required for the Maintenance of Metaphase Chromosome Alignment in Drosophila

Yucel

Marszalek

McIntosh

et al. 2000

The Journal of Cell Biology

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CENP-meta has been identified as an essential, kinesin-like motor protein in Drosophila. The 257-kD CENP-meta protein is most similar to the vertebrate kinetochore-associated kinesin-like protein CENP-E, and like CENP-E, is shown to be a component of centromeric/kinetochore regions of Drosophila chromosomes. However, unlike CENP-E, which leaves the centromere/kinetochore region at the end of anaphase A, the CENP-meta protein remains associated with the centromeric/kinetochore region of the chromosome during all stages of the Drosophila cell cycle. P-element–mediated disruption of the CENP-meta gene leads to late larval/pupal stage lethality with incomplete chromosome alignment at metaphase. Complete removal of CENP-meta from the female germline leads to lethality in early embryos resulting from defects in metaphase chromosome alignment. Real-time imaging of these mutants with GFP-labeled chromosomes demonstrates that CENP-meta is required for the maintenance of chromosomes at the metaphase plate, demonstrating that the functions required to establish and maintain chromosome congression have distinguishable requirements.

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Active MAP Kinase in Mitosis: Localization at Kinetochores and Association with the Motor Protein CENP-E

Cited by 206 publications

References 63 publications

Role of MEK/ERK pathway in the MAD2-mediated cisplatin sensitivity in testicular germ cell tumour cells

Role of MEK/ERK pathway in the MAD2-mediated cisplatin sensitivity in testicular germ cell tumour cells

Inhibitors of the PI3‐kinase/Akt pathway induce mitotic catastrophe in non‐small cell lung cancer cells

CENP-meta, an Essential Kinetochore Kinesin Required for the Maintenance of Metaphase Chromosome Alignment in Drosophila

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