The dynamics of signal amplification by macromolecular assemblies for the control of chromosome segregation

Lee, Semin; Bolaños-García, Víctor M.

doi:10.3389/fphys.2014.00368

Cited by 3 publications

(3 citation statements)

References 144 publications

(201 reference statements)

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“…The kinetochore not only provides this physical linkage but is also endowed with spring-like properties that enable it to respond to tension that through the spindle assembly checkpoint (SAC) can signal and correct improper MT attachments. It also acts as a platform for the loading of the SAC proteins and of motor and other MT-associated proteins that regulate behaviour of the MT plus ends and chromosome movement (reviewed in [2][3][4][5]). To fully understand these multiple properties, it is necessary to obtain precise structural information of how the kinetochore is built.…”

Section: Introductionmentioning

confidence: 99%

Network of protein interactions within the Drosophila inner kinetochore

et al. 2016

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The kinetochore provides a physical connection between microtubules and the centromeric regions of chromosomes that is critical for their equitable segregation. The trimeric Mis12 sub-complex of the Drosophila kinetochore binds to the mitotic centromere using CENP-C as a platform. However, knowledge of the precise connections between Mis12 complex components and CENP-C has remained elusive despite the fundamental importance of this part of the cell division machinery. Here, we employ hydrogen–deuterium exchange coupled with mass spectrometry to reveal that Mis12 and Nnf1 form a dimer maintained by interacting coiled-coil (CC) domains within the carboxy-terminal parts of both proteins. Adjacent to these interacting CCs is a carboxy-terminal domain that also interacts with Nsl1. The amino-terminal parts of Mis12 and Nnf1 form a CENP-C-binding surface, which docks the complex and thus the entire kinetochore to mitotic centromeres. Mutational analysis confirms these precise interactions are critical for both structure and function of the complex. Thus, we conclude the organization of the Mis12–Nnf1 dimer confers upon the Mis12 complex a bipolar, elongated structure that is critical for kinetochore function.

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Section: Introductionmentioning

confidence: 99%

Network of protein interactions within the Drosophila inner kinetochore

et al. 2016

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“…An additional layer of complexity in SAC regulation is represented by the extent of post-translational modifications of SAC components, including BubR1, in which phosphorylation, acetylation and ubiquitylation affect the stability, reversibility, subcellular localisation, turnover, and hierarchical order of assembly/disassembly of SAC subcomplexes [47][48][49]. For instance, in prometaphase, BubR1 is acetylated by the histone acetyltransferase P300/CBP-associated factor (PCAF) at residue K250, a modification that protects BubR1 from degradation by APC/C-Cdc20 [50,51].…”

Section: The Importance Of Post-translational Modificationsmentioning

confidence: 99%

BubR1 kinase: protection against aneuploidy and premature aging

Kapanidou

Lee

Bolaños-García

2015

Trends in Molecular Medicine

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The multidomain protein kinase BubR1 is a central component of the mitotic spindle assembly checkpoint (SAC), an essential self-monitoring system of the eukaryotic cell cycle that ensures the high fidelity of chromosome segregation by delaying the onset of anaphase until all chromosomes are properly bi-oriented on the mitotic spindle. We discuss the roles of BubR1 in the SAC and the implications of BubR1-mediated interactions that protect against aneuploidy. We also describe the emerging roles of BubR1 in cellular processes that extend beyond the SAC, discuss how mice models have revealed unanticipated functions for BubR1 in the regulation of normal aging, and the potential role of BubR1 as therapeutic target for the development of innovative anticancer therapies.

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“…Multiple studies indicate that tumors are particularly dependent on redox-regulating pathways and that this vulnerability can be exploited by targeted therapeutics (18,19). In recent years, several kinases have been identified that regulate the sensitivity of cancer cells to paclitaxel by inhibiting centrosome splitting (20) or enhancing microtubule stability (21,22). Much less attention has been given to kinases that affect paclitaxel sensitivity by modulating cancer cell metabolism.…”

Section: Introductionmentioning

confidence: 99%

6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase-2 Regulates TP53-Dependent Paclitaxel Sensitivity in Ovarian and Breast Cancers

Yang

Zhang

Jiang

et al. 2019

Clinical Cancer Research

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Purpose: Paclitaxel is an integral component of primary therapy for breast and epithelial ovarian cancers, but less than half of these cancers respond to the drug. Enhancing the response to primary therapy with paclitaxel could improve outcomes for women with both diseases.Experimental Design: Twelve kinases that regulate metabolism were depleted in multiple ovarian and breast cancer cell lines to determine whether they regulate sensitivity to paclitaxel in Sulforhodamine B assays. The effects of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2) depletion on cell metabolomics, extracellular acidification rate, nicotinamide adenine dinucleotide phosphate, reactive oxygen species (ROS), and apoptosis were studied in multiple ovarian and breast cancer cell lines. Four breast and ovarian human xenografts and a breast cancer patient-derived xenograft (PDX) were used to examine the knockdown effect of PFKFB2 on tumor cell growth in vivo.Results: Knockdown of PFKFB2 inhibited clonogenic growth and enhanced paclitaxel sensitivity in ovarian and breast cancer cell lines with wild-type TP53 (wtTP53). Silencing PFKFB2 significantly inhibited tumor growth and enhanced paclitaxel sensitivity in four xenografts derived from two ovarian and two breast cancer cell lines, and prolonged survival in a triple-negative breast cancer PDX. Transfection of siPFKFB2 increased the glycolysis rate, but decreased the flow of intermediates through the pentosephosphate pathway in cancer cells with wtTP53, decreasing NADPH. ROS accumulated after PFKFB2 knockdown, which stimulated Jun N-terminal kinase and p53 phosphorylation, and induced apoptosis that depended upon upregulation of p21 and Puma.Conclusions: PFKFB2 is a novel target whose inhibition can enhance the effect of paclitaxel-based primary chemotherapy upon ovarian and breast cancers retaining wtTP53.

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The dynamics of signal amplification by macromolecular assemblies for the control of chromosome segregation

Cited by 3 publications

References 144 publications

Network of protein interactions within the Drosophila inner kinetochore

Network of protein interactions within the Drosophila inner kinetochore

BubR1 kinase: protection against aneuploidy and premature aging

6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase-2 Regulates TP53-Dependent Paclitaxel Sensitivity in Ovarian and Breast Cancers

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