Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:3.6.4.4 (kinesin)
5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitotic polo-like kinases have been implicated in the formation and function of bipolar spindles on the basis of their respective localizations and mutant phenotypes. To date, this putative regulation has been limited to a kinesin-like motor protein, a centrosomal structural protein, and two microtubule-associated proteins (MAPs). In this study, another spindle-regulating protein, the mammalian non-MAP microtubule-binding and -stabilizing protein, the translationally controlled tumor protein (TCTP), was identified as a putative Plk-interacting clone by a two-hybrid screen. Plk phosphorylates TCTP on two serine residues in vitro and cofractionates with the majority of kinase activity toward TCTP in mitotic cell lysates. In addition, these sites were demonstrated to be phosphorylated in vivo. Overexpression of a Plk phosphorylation site-deficient mutant of TCTP induced a dramatic increase in the number of multinucleate cells, rounded cells with condensed ball-like nuclei, and cells undergoing cell death, similar to both the reported anti-Plk antibody microinjection and the low-concentration taxol treatment phenotypes. These results suggest that phosphorylation decreases the microtubule-stabilizing activity of TCTP and promotes the increase in microtubule dynamics that occurs after metaphase.
...
PMID:Plk phosphorylation regulates the microtubule-stabilizing protein TCTP. 1216 14

We have investigated the function of mitotic kinesin-like protein (MKlp) 2, a kinesin localized to the central spindle, and demonstrate that its depletion results in a failure of cleavage furrow ingression and cytokinesis, and disrupts localization of polo-like kinase 1 (Plk1). MKlp2 is a target for Plk1, and phosphorylated MKlp2 binds to the polo box domain of Plk1. Plk1 also binds directly to microtubules and targets to the central spindle via its polo box domain, and this interaction controls the activity of Plk1 toward MKlp2. An antibody to the neck region of MKlp2 that prevents phosphorylation of MKlp2 by Plk1 causes a cytokinesis defect when introduced into cells. We propose that phosphorylation of MKlp2 by Plk1 is necessary for the spatial restriction of Plk1 to the central spindle during anaphase and telophase, and the complex of these two proteins is required for cytokinesis.
...
PMID:Phosphorylation of mitotic kinesin-like protein 2 by polo-like kinase 1 is required for cytokinesis. 1293 56

Here we describe methods for the characterization of the kinesin-9 family motor protein Rabkinesin-6/Rab6-KIFL/MKlp2 in cytokinesis. Here we outline biochemical assays for studying the interaction of Rabkinesin-6/Rab6-KIFL/MKlp2 with microtubules, and its regulation and interaction with the mitotic polo-like kinase 1 using recombinant proteins expressed in and purified from insect cells. Protocols for the in vivo functional analysis of Rabkinesin-6/Rab6-KIFL/MKlp2 using depletion with small interfering RNA duplexes are described.
...
PMID:Assay and functional properties of Rabkinesin-6/Rab6-KIFL/MKlp2 in cytokinesis. 1647 25

siRNAs that specifically silence the expression of cancer-related genes offer a therapeutic approach in oncology. However, it remains critical to determine the true mechanism of their therapeutic effects. Here, we describe the preclinical development of chemically modified siRNA targeting the essential cell-cycle proteins polo-like kinase 1 (PLK1) and kinesin spindle protein (KSP) in mice. siRNA formulated in stable nucleic acid lipid particles (SNALP) displayed potent antitumor efficacy in both hepatic and subcutaneous tumor models. This was correlated with target gene silencing following a single intravenous administration that was sufficient to cause extensive mitotic disruption and tumor cell apoptosis. Our siRNA formulations induced no measurable immune response, minimizing the potential for nonspecific effects. Additionally, RNAi-specific mRNA cleavage products were found in tumor cells, and their presence correlated with the duration of target mRNA silencing. Histological biomarkers confirmed that RNAi-mediated gene silencing effectively inhibited the target's biological activity. This report supports an RNAi-mediated mechanism of action for siRNA antitumor effects, suggesting a new methodology for targeting other key genes in cancer development with siRNA-based therapeutics.
...
PMID:Confirming the RNAi-mediated mechanism of action of siRNA-based cancer therapeutics in mice. 1930 98

In mammalian cultured cells the initiation of cytokinesis is regulated - both temporally and spatially - by the overlapping, anti-parallel microtubules of the spindle midzone. This region recruits several key central spindle components: PRC-1, polo-like kinase 1 (Plk-1), the centralspindlin complex, and the chromosome passenger complex (CPC), which together serve to stabilize the microtubule overlap, and also to coordinate the assembly of the cortical actin/myosin cytoskeleton necessary to physically cleave the cell in two. The localization of these crucial elements to the spindle midzone requires members of the kinesin superfamily of microtubule-based motor proteins. Here we focus on reviewing the role played by a variety of kinesins in both building and operating the spindle midzone machinery during cytokinesis.
...
PMID:Kinesins to the core: The role of microtubule-based motor proteins in building the mitotic spindle midzone. 2010 73

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.
...
PMID:Cell cycle-dependent cytotoxicity and mitotic spindle checkpoint dependency of investigational and approved antimitotic agents. 2138 2

Small interfering RNAs (siRNAs) are emerging as promising therapeutic tools. However, the widespread clinical application of such molecules as modulators of gene expression is still dependent on several aspects that limit their bioavailability. One of the most promising strategies to overcome the barriers faced by gene silencing molecules involves the use of lipid-based nanoparticles (LNPs) and viral vectors, such as adenoviruses (Ads). The primary obstacle for translating gene silencing technology from an effective research tool into a feasible therapeutic strategy remains its efficient delivery to the targeted cell type in vivo. In this study, we tested the capability of LNPs and Ad to transduce and treat locally tumors in vivo. Efficient knockdown of a surrogate reporter (luciferase) and therapeutic target genes such as the kinesin spindle protein (KIF11) and polo-like kinase 1 were observed. Most importantly, this activity led to a cell cycle block as a consequence and slowed down tumor progression in tumor-bearing animals. Our data indicate that it is possible to achieve tumor transduction with si/short hairpin RNAs and further improve the delivery strategy that likely in the future will lead to the ideal non-viral particle for targeted cancer gene silencing.
...
PMID:Intratumor RNA interference of cell cycle genes slows down tumor progression. 2139 70

Many mitotic kinases are both critical for maintaining genome stability and are important targets for anticancer therapies. We provide evidence that SIK3 (salt-inducible kinase 3), an AMP-activated protein kinase-related kinase, is important for mitosis to occur properly in mammalian cells. Downregulation of SIK3 resulted in an extension of mitosis in both mouse and human cells but did not affect the DNA damage checkpoint. Time-lapse microscopy and other approaches indicated that mitotic exit but not mitotic entry was delayed. Although repression of SIK3 alone simply delayed mitotic exit, it was able to sensitize cells to various antimitotic chemicals. Both mitotic arrest and cell death caused by spindle poisons were enhanced after SIK3 depletion. Likewise, the antimitotic effects due to pharmacological inhibition of mitotic kinases including Aurora A, Aurora B, and polo-like kinase 1 were enhanced in the absence of SIK3. Finally, in addition to promoting the sensitivity of a small-molecule inhibitor of the mitotic kinesin Eg5, SIK3 depletion was able to overcome cells that developed drug resistance. These results establish the importance of SIK3 as a mitotic regulator and underscore the potential of SIK3 as a druggable antimitotic target.
...
PMID:Salt-inducible kinase 3 is a novel mitotic regulator and a target for enhancing antimitotic therapeutic-mediated cell death. 2474 32

Mammalian erythroblasts undergo enucleation through a process thought to be similar to cytokinesis. Microtubule-organizing centers (MTOCs) mediate organization of the mitotic spindle apparatus that separates the chromosomes during mitosis and are known to be crucial for proper cytokinesis. However, the role of MTOCs in erythroblast enucleation remains unknown. We therefore investigated the effect of various MTOC inhibitors on cytokinesis and enucleation using human colony-forming units-erythroid (CFU-Es) and mature erythroblasts generated from purified CD34(+) cells. We found that erythro-9-[3-(2-hydroxynonyl)]adenine (EHNA), a dynein inhibitor, and monastrol, a kinesin Eg5 inhibitor, as well as various inhibitors of MTOC regulators, including ON-01910 (Plk-1), MLN8237 (aurora A), hesperadin (aurora B), and LY294002 (PI3K), all inhibited CFU-E cytokinesis. Among these inhibitors, however, only EHNA blocked enucleation. Moreover, terminally differentiated erythroblasts expressed only dynein; little or none of the other tested proteins was detected. Over the course of the terminal differentiation of human erythroblasts, the fraction of cells with nuclei at the cell center declined, whereas the fraction of polarized cells, with nuclei shifted to a position near the plasma membrane, increased. Dynein inhibition impaired nuclear polarization, thereby blocking enucleation. These data indicate that dynein plays an essential role not only in cytokinesis but also in enucleation. We therefore conclude that human erythroblast enucleation is a process largely independent of MTOCs, but dependent on dynein.
...
PMID:Erythroblast enucleation is a dynein-dependent process. 2672 40

Hyaluronan is an extracellular matrix component that absorbs water in tissues and engages cell surface receptors, like Cluster of Differentiation 44 (CD44), to promote cellular growth and movement. Consequently, CD44 demarks stem cells in normal tissues and tumor-initiating cells isolated from neoplastic tissues. Hyaluronan mediated motility receptor (HMMR, also known as RHAMM) is another one of few defined hyaluronan receptors. HMMR is also associated with neoplastic processes and its role in cancer progression is often attributed to hyaluronan-mediated signaling. But, HMMR is an intracellular, microtubule-associated, spindle assembly factor that localizes protein complexes to augment the activities of mitotic kinases, like polo-like kinase 1 and Aurora kinase A, and control dynein and kinesin motor activities. Expression of HMMR is elevated in cells prior to and during mitosis and tissues with detectable HMMR expression tend to be highly proliferative, including neoplastic tissues. Moreover, HMMR is a breast cancer susceptibility gene product. Here, we briefly review the associations between HMMR and tumorigenesis as well as the structure and evolution of HMMR, which identifies Hmmr-like gene products in several insect species that do not produce hyaluronan. This review supports the designation of HMMR as a homeostasis, mitosis, and meiosis regulator, and clarifies how its dysfunction may promote the tumorigenic process and cancer progression.
...
PMID:Hyaluronan Mediated Motility Receptor (HMMR) Encodes an Evolutionarily Conserved Homeostasis, Mitosis, and Meiosis Regulator Rather than a Hyaluronan Receptor. 3223 Oct 69


1 2 Next >>

---