High Mitotic Activity of Polo-like Kinase 1 Is Required for Chromosome Segregation and Genomic Integrity in Human Epithelial Cells

Lera, Robert F.; Burkard, Mark E.

doi:10.1074/jbc.m112.412544

Cited by 48 publications

(62 citation statements)

References 42 publications

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“…However, these newer anti-mitotic agents may still be able to mimic the chromosome missegregation caused by paclitaxel if dosed continuously at low levels. This effect occurs, for example, from partial loss of polo-like kinase 1 activity (51). …”

Section: Discussionmentioning

confidence: 99%

Cytotoxicity of Paclitaxel in Breast Cancer Is due to Chromosome Missegregation on Multipolar Spindles

et al. 2014

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The blockbuster chemotherapy drug paclitaxel is widely presumed to cause cell death in tumors as a consequence of mitotic arrest, as it does at concentrations routinely used in cell culture. However, we determine here that paclitaxel levels in primary breast tumors are well below those required to elicit sustained mitotic arrest. Instead, cells in these lower concentrations of drug proceed through mitosis without substantial delay and divide their chromosomes on multipolar spindles, resulting in chromosome missegregation and cell death. Consistent with these cell culture data, the majority of mitotic cells in primary human breast cancers contain multipolar spindles after paclitaxel treatment. Contrary to the previous hypothesis, we find that mitotic arrest is dispensable for tumor regression in patients. These results demonstrate that mitotic arrest is not responsible for the efficacy of paclitaxel, which occurs due to chromosome missegregation on highly abnormal, multipolar spindles. This mechanistic insight may be used to improve selection of future anti-mitotic drugs and to identify a biomarker with which to select patients likely to benefit from paclitaxel.

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Section: Discussionmentioning

confidence: 99%

Cytotoxicity of Paclitaxel in Breast Cancer Is due to Chromosome Missegregation on Multipolar Spindles

et al. 2014

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“…In contrast, downregulation of Plk1 is mediated by the ubiquitin-proteasome system, involving APC/C-Cdh1 or -Cdc20, during the late M and G 1 phases (2,4). Consistent with the diverse roles of Plk1 in mitosis, inhibition of Plk1 leads to multiple mitotic defects, including aberrant spindle formation, misaligned chromosomes, and improper chromosome condensation (5)(6)(7). In addition, Plk1 is highly upregulated in tumors and inhibition of its activity induces apoptosis in cancer cells, but not in normal cells (4,8).…”

Section: Introductionmentioning

confidence: 96%

CIP2A Modulates Cell-Cycle Progression in Human Cancer Cells by Regulating the Stability and Activity of Plk1

Kim

et al. 2013

Cancer Research

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Abnormal cell-cycle control can lead to aberrant cell proliferation and cancer. The oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) is an inhibitor of protein phosphatase 2A (PP2A) that stabilizes c-Myc. However, the precise role of CIP2A in cell division is not understood. Herein, we show that CIP2A is required for mitotic progression by regulating the polo-like kinase (Plk1). With mitotic entry, CIP2A translocated from the cytoplasm to the nucleus, where it was enriched at spindle poles. CIP2A depletion delayed mitotic progression, resulting in mitotic abnormalities independent of PP2A activity. Unexpectedly, CIP2A interacted directly with the polo-box domain of Plk1 during mitosis. This interaction was required to maintain Plk1 stability by blocking APC/C-Cdh1-dependent proteolysis, thereby enhancing the kinase activity of Plk1 during mitosis. We observed strong correlation and in vivo interactions between these two proteins in multiple human cancer specimens. Overall, our results established a novel function for CIP2A in facilitating the stability and activity of the pivotal mitotic kinase Plk1 in cell-cycle progression and tumor development. Cancer Res; 73(22); 6667-78. Ó2013 AACR.

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“…For instance, different levels of activity of cyclin-dependent kinase elicit entry into S phase and into mitosis. 34 Similarly, distinct levels of Polo-like kinase are required for mitosis and cytokinesis, 35 and different levels of Aurora kinase underlie its functions in chromosome compaction and in regulation of kinetochoremicrotubule interaction. 36 It is also interesting to note that the Pom1-related kinase DYRK1A, which lies within the critical region of human chromosome 21 involved in trisomy, is highly dosage-sensitive, exhibiting both haploinsufficiency and duplication phenotypes in brain growth, though its mode of action appears distinct from that of Pom1.…”

Section: Pom1 Inhibits Cdr2 Through Its C-terminal Tailmentioning

confidence: 99%

Distinct levels in Pom1 gradients limit Cdr2 activity and localization to time and position division

et al. 2013

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High Mitotic Activity of Polo-like Kinase 1 Is Required for Chromosome Segregation and Genomic Integrity in Human Epithelial Cells

Cited by 48 publications

References 42 publications

Cytotoxicity of Paclitaxel in Breast Cancer Is due to Chromosome Missegregation on Multipolar Spindles

Cytotoxicity of Paclitaxel in Breast Cancer Is due to Chromosome Missegregation on Multipolar Spindles

CIP2A Modulates Cell-Cycle Progression in Human Cancer Cells by Regulating the Stability and Activity of Plk1

Distinct levels in Pom1 gradients limit Cdr2 activity and localization to time and position division

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