Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.4.4 (kinesin)
 5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aurora kinases representing a novel family of serine/threonine kinases have been identified as key regulators of the mitotic cell division process. The three members of this kinase family, identified so far, referred to as Aurora-A, Aurora-B and Aurora-C kinases, are close homologues of the prototypic yeast Ipll and Drosophila aurora kinases, which are known to be involved in the regulation of centrosome function, bipolar spindle assembly and chromosome segregation processes. All three members of the mammalian kinase family have a catalytic domain that is highly conserved with a short C-terminal domain and an N-terminal domain of varying sizes. Following their discovery about five years ago, extensive research has focused on understanding the biological roles of these kinases and elucidation of their pathways, which regulate cell proliferation and maintenance of normal cellular phenotypes. Significant interest in the subject was generated since all three Aurora kinases family members were reported to be overexpressed in many human cancers, and elevated expression has been correlated with chromosomal instability and clinically aggressive disease in some instances. Ectopic overexpression of one member of the family, Aurora-A, was shown to induce oncogenic transformation in cells. Unlike most other putative oncogenes identified, so far, members of this kinase family are expressed and active at the highest level during G2-M phase of the cell cycle. Aurora kinases are localized at the centrosomes of interphase cells, at the poles of the bipolar spindle and in the midbody of the mitotic apparatus. Substrates identified for the Aurora-A and Aurora-B kinases, include a kinesin-like motor protein, spindle apparatus proteins, histone H3 protein, kinetochore protein and the tumor suppressor protein p53. Identification of Aurora kinases as RasGAP Src homology 3 domain binding protein, also implicates these kinases as potential effectors in the Ras pathway relevant to oncogenesis. Abnormal elevated expression of Aurora kinases detected in human cancer cells could help explain the underlying biological mechanisms responsible for the development of many cellular phenotypes associated with malignant cells. Identification of these mechanisms offers the possibility of designing novel targeted therapies for cancer in the future.
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PMID:The Aurora kinases: role in cell transformation and tumorigenesis. 1288 18

Mitotic Centromere-Associated Kinesin (MCAK) is a member of the kinesin-13 subfamily of kinesin-related proteins. In mitosis, this microtubule-depolymerising kinesin seems to be implicated in chromosome segregation and in the correction of improper kinetochore-microtubule interactions, and its activity is regulated by the Aurora-B kinase. However, there are no published data on its behaviour and function during mammalian meiosis. We have analysed by immunofluorescence in squashed mouse spermatocytes, the distribution and possible function of MCAK, together with Aurora-B, during both meiotic divisions. Our results demonstrate that MCAK and Aurora-B colocalise at the inner domain of metaphase I centromeres. Thus, MCAK shows a "cone"-like three-dimensional distribution beneath and surrounding the closely associated sister kinetochores. During the second meiotic division, MCAK and Aurora-B also colocalise at the inner centromere domain as a band that joins sister kinetochores, but only during prometaphase II in unattached chromosomes. During chromosome congression to the metaphase II plate, MCAK relocalises and appears as a ring below each sister kinetochore. Aurora-B also relocalises to appear as a ring surrounding and beneath kinetochores but during late metaphase II. Our results demonstrate that the redistribution of MCAK at prometaphase II/metaphase II centromeres depends on tension across the centromere and/or on the interaction of microtubules with kinetochores. We propose that the perikinetochoric rings of MCAK and Aurora-B define a novel transient centromere domain at least in mouse chromosomes during meiosis. We discuss the possible functions of MCAK at the inner centromere domain and at the perikinetochoric ring during both meiotic divisions.
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PMID:A perikinetochoric ring defined by MCAK and Aurora-B as a novel centromere domain. 1674 59

The survival of eukaryotes depends on the accurate coordination of mitosis with cytokinesis. Key for the coordination of both processes is the chromosomal passenger complex (CPC) comprising Aurora-B, INCENP, survivin, and borealin. The translocation of the CPC from centromeres to the spindle midzone, a structure composed of antiparallel microtubules, at anaphase onset is critical for the completion of cytokinesis. In mammalian cells, the mitotic kinesin Mklp2 is essential for recruitment of the CPC to the spindle midzone. However, the mechanism regulating the binding of Mklp2 to microtubules has remained unknown. Here, we demonstrate that Mklp2 and the CPC mutually depend on each other for midzone localization; i.e., Mklp2 is mislocalized in INCENP-RNAi cells and vice versa. Remarkably, INCENP is required for localization of Mklp2 to the ends of stable microtubules in cells with low Cdk1 activity. In vitro assays revealed that the association between the CPC and Mklp2 is negatively regulated by Cdk1. Collectively, our data suggest that anaphase onset triggers the association between the CPC and Mklp2 and that this association targets the CPC-Mklp2 complex to the ends of stable microtubules in the spindle midzone.
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PMID:Cdk1 negatively regulates midzone localization of the mitotic kinesin Mklp2 and the chromosomal passenger complex. 1930 98

The mitotic spindle checkpoint (SPC) is a highly regulated mechanism in eukaryotic cells that ensures the even distribution of the duplicated genome between daughter cells. Malfunction of the SPC or deregulated expression of SPC regulatory proteins is frequently associated with a poor response to chemotherapeutic agents. We investigated various approved and investigational mitosis-specific agents, including spindle poisons, an Eg5 kinesin inhibitor, inhibitors of polo-like kinase 1 (Plk1) or Aurora-B kinase, a benzamide class HDAC inhibitor and compounds identified in a chemical genetics screen for their cell cycle-dependent cytotoxicities and for their activities toward SPC deficient (HT29, Caco-2, T47D) and SPC proficient human cell lines (A2780, HCT116, SW480). Using the RKOp27 cell system that allows inducible cell cycle arrest by the tunable expression of the cdk inhibitor p27Kip1, we found an exquisite proliferation-dependent cytotoxicity for all compounds except the aurora kinase inhibitor VX-680. Cytotoxicity of the antimitotic compounds was in general higher on SPC proficient than on deficient cells. We found two exceptions, a benzamide HDAC inhibitor which was effective on SPC proficient and deficient cells and an investigational compound, BYK72767, with a yet unknown mode of action. The degree of increased mitotic index was no predictor of cytotoxicity of the compounds nor was the phosphorylation of BubR1. However, SPC deficient cell lines were able to tolerate mitotic arrest for far longer times than SPC proficient cells. We conclude that targeting of SPC deficient cancers with novel antimitotic principles remains a challenge but certain drug classes may be equally efficacious regardless of SPC status.
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PMID:Cell cycle-dependent cytotoxicity and mitotic spindle checkpoint dependency of investigational and approved antimitotic agents. 2138 2

Cell division with partitioning of the genetic material should take place only when paired chromosomes named bivalents (meiosis I) or sister chromatids (mitosis and meiosis II) are correctly attached to the bipolar spindle in a tension-generating manner. For this to happen, the spindle assembly checkpoint (SAC) checks whether unattached kinetochores are present, in which case anaphase onset is delayed to permit further establishment of attachments. Additionally, microtubules are stabilized when they are attached and under tension. In mitosis, attachments not under tension activate the so-named error correction pathway depending on Aurora B kinase substrate phosphorylation. This leads to microtubule detachments, which in turn activates the SAC [1-3]. Meiotic divisions in mammalian oocytes are highly error prone, with severe consequences for fertility and health of the offspring [4, 5]. Correct attachment of chromosomes in meiosis I leads to the generation of stretched bivalents, but-unlike mitosis-not to tension between sister kinetochores, which co-orient. Here, we set out to address whether reduction of tension applied by the spindle on bioriented bivalents activates error correction and, as a consequence, the SAC. Treatment of oocytes in late prometaphase I with Eg5 kinesin inhibitor affects spindle tension, but not attachments, as we show here using an optimized protocol for confocal imaging. After Eg5 inhibition, bivalents are correctly aligned but less stretched, and as a result, Aurora-B/C-dependent error correction with microtubule detachment takes place. This loss of attachments leads to SAC activation. Crucially, SAC activation itself does not require Aurora B/C kinase activity in oocytes.
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PMID:Tension-Induced Error Correction and Not Kinetochore Attachment Status Activates the SAC in an Aurora-B/C-Dependent Manner in Oocytes. 2927 28

Breast cancer is the most common cancer type in females, and exploring the mechanisms of disease progression is playing a crucial role in the development of potential therapeutics. Pituitary tumor-transforming gene (PTTG) family members are well documented to be involved in cell-cycle regulation and mitosis, and contribute to cancer development by their involvement in cellular transformation in several tumor types. The critical roles of PTTG family members as crucial transcription factors in diverse types of cancers are recognized, but how they regulate breast cancer development still remains mostly unknown. Meanwhile, a holistic genetic analysis exploring whether PTTG family members regulate breast cancer progression via the cell cycle as well as the energy metabolism-related network is lacking. To comprehensively understand the messenger RNA expression profiles of PTTG proteins in breast cancer, we herein conducted a high-throughput screening approach by integrating information from various databases such as Oncomine, Kaplan-Meier Plotter, Metacore, ClueGo, and CluePedia. These useful databases and tools provide expression profiles and functional analyses. The present findings revealed that PTTG1 and PTTG3 are two important genes with high expressions in breast cancer relative to normal breast cells, implying their unique roles in breast cancer progression. Results of our coexpression analysis demonstrated that PTTG family genes were positively correlated with thiamine triphosphate (TTP), deoxycytidine triphosphate (dCTP) metabolic, glycolysis, gluconeogenesis, and cell-cycle related pathways. Meanwhile, through Cytoscape analyzed indicated that in addition to the metastasis markers AURKA, AURKB, and NDC80, many of the kinesin superfamily (KIF) members including KIFC1, KIF2C, KIF4A, KIF14, KIF20A, KIF23, were also correlated with PTTG family transcript expression. Finally, we revealed that high levels of PTTG1 and PTTG3 transcription predicted poor survival, which provided useful insights into prospective research of cancer associated with the PTTG family. Therefore, these members of the PTTG family would serve as distinct and essential prognostic biomarkers in breast cancer.
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PMID:Gene signatures and prognostic analyses of the Tob/BTG pituitary tumor-transforming gene (PTTG) family in clinical breast cancer patients. 3317 33