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)

Pancreatic cancer is a devastating disease with a high mortality rate. Treatment of this malignancy remains a big challenge in oncology, and none of the currently available chemotherapeutic agents has a remarkable impact on improving patient survival. Consequently, it is important to explore new targets and find effective drugs for the management of this disease. Here we report that inhibition of the mitotic kinesin Eg5 by a pharmacological compound effectively prevents the proliferation of pancreatic cancer cells by halting mitotic progression, resulting in robust apoptosis. The mitotic arrest induced by this agent is attributed to its interference with spindle formation and activation of the spindle checkpoint. Impairment of the spindle checkpoint significantly compromises both mitotic arrest and apoptosis induced by the Eg5 inhibitor, suggesting the importance of the spindle checkpoint in monitoring Eg5 inhibitor sensitivity. Furthermore, treatment of nude mice bearing tumor xenografts of human pancreatic cancer results in pronounced tumor regression by triggering apoptosis. These data thus indicate Eg5 as a potential target for pancreatic cancer treatment.
...
PMID:Validating the mitotic kinesin Eg5 as a therapeutic target in pancreatic cancer cells and tumor xenografts using a specific inhibitor. 1853 63

In most organisms, kinesin-5 motors are essential for mitosis and meiosis, where they crosslink and slide apart the antiparallel microtubule half-spindles. Recently, it was shown using single-molecule optical trapping that a truncated, double-headed human kinesin-5 dimer can step processively along microtubules. However, processivity is limited ( approximately 8 steps) with little coordination between the heads, raising the possibility that kinesin-5 motors might also be able to move by a nonprocessive mechanism. To investigate this, we engineered single-headed kinesin-5 dimers. We show that a set of these single-headed Eg5 dimers drive microtubule sliding at about 90% of wild-type velocity, indicating that Eg5 can slide microtubules by a mechanism in which one head of each Eg5 head-pair is effectively redundant. On the basis of this, we propose a muscle-like model for Eg5-driven microtubule sliding in spindles in which most force-generating events are single-headed interactions and alternate-heads processivity is rare.
...
PMID:Single-headed mode of kinesin-5. 1855 67

Despite the high level of similarity in structural organisation of their motor domains and, consequently, in the mechanism of motility generation, kinesin-5 moves about 25-fold slower than conventional kinesin (kinesin-1). To elucidate the structural motifs contributing to velocity regulation, we expressed a set of Eg5- and KIF5A-based chimeric proteins with interchanged native neck linker and neck elements. Among them, the chimera consisting of the Eg5 catalytic core (residues 1-357) fused to the KIF5A linker and neck (residues 326-450) displayed increased velocity compared to the Eg5 control protein. This is the first evidence that the velocity of the slow-moving motor Eg5 can be elevated by insertion of neck linker and neck elements taken from a fast-moving motor. Whereas the complementary chimera composed of the KIF5A core (1-325) and the Eg5 linker and neck (358-513) was found to be immotile, insertion of the first half-KIF5A linker into this chimera restored motility. Our results indicate that the neck linker and the neck are involved not only in motility generation in general and in determination of movement direction, but also in velocity regulation.
...
PMID:The role of Kinesin neck linker and neck in velocity regulation. 1864 Jan 25

Although assembly of the mitotic spindle is known to be a precisely controlled process, regulation of the key motor proteins involved remains poorly understood. In eukaryotes, homotetrameric kinesin-5 motors are required for bipolar spindle formation. Eg5, the vertebrate kinesin-5, has two modes of motion: an adenosine triphosphate (ATP)-dependent directional mode and a diffusive mode that does not require ATP hydrolysis. We use single-molecule experiments to examine how the switching between these modes is controlled. We find that Eg5 diffuses along individual microtubules without detectable directional bias at close to physiological ionic strength. Eg5's motility becomes directional when bound between two microtubules. Such activation through binding cargo, which, for Eg5, is a second microtubule, is analogous to known mechanisms for other kinesins. In the spindle, this might allow Eg5 to diffuse on single microtubules without hydrolyzing ATP until the motor is activated by binding to another microtubule. This mechanism would increase energy and filament cross-linking efficiency.
...
PMID:Microtubule cross-linking triggers the directional motility of kinesin-5. 1867 7

XB-S is a protein with an amino-terminal-truncated form of tenascin-X (TNXB). However, the precise roles of XB-S in vivo are unknown. In this study, to determine the role of XB-S in vivo, we screened XB-S-binding proteins. FLAG-tagged XB-S was transiently introduced into 293T cells. Then its associated proteins were purified by immunoprecipitation using an anti-FLAG antibody and its components were identified by mass spectrometric analyses. Mitotic motor kinesin Eg5 was identified in the immunoprecipitates. XB-S and Eg5 proteins were co-localized in the cytoplasm in interphase and mitosis, but XB-S did not localize on mitotic spindle microtubules, on which Eg5 prominently localized in mitosis. As for Eg5 binding to XB-S, glutathione S-transferase-fused XB-S expressed in vitro directly bound to full-length Eg5 translated in reticulocyte lysate, and the XB-S-binding region was located in the motor domain of Eg5. Furthermore, during cell cycle progression XB-S showed a similar expression profile to that of Eg5. These results suggest possible involvement of XB-S in the function of Eg5.
...
PMID:Truncated form of tenascin-X, XB-S, interacts with mitotic motor kinesin Eg5. 1867 83

The kinesin spindle protein (KSP, also known as Hs Eg5) plays an essential part in the proper separation of spindle poles and the correct formation of bipolar mitotic spindle during mitosis. Inhibition of this protein results in cells apoptosis followed by mitotic arrest and the formation of characteristic monoaster spindles. Compared with the traditional chemotherapeutic agents (taxanes, vinca alkaloids), KSP inhibitors (KSPi) will not lead to the neuropathic side effects, so KSP has become a novel and an attractive anticancer target. Accordingly, more and more interest has been focused on the development of high effective and selective KSPi. This review will focus on some kinds of KSPi on the basis of introducing structure and function of KSP.
...
PMID:Progress on kinesin spindle protein inhibitors as anti-cancer agents. 1869 Aug 30

The proper assembly and operation of the mitotic spindle is essential to ensure the accurate segregation of chromosomes and to position the cytokinetic furrow during cell division in eukaryotes. Not only are dynamic microtubules required but also the concerted actions of multiple motor proteins are necessary to effect spindle pole separation, chromosome alignment, chromatid segregation, and spindle elongation. Although a number of motor proteins are known to play a role in mitosis, there remains a limited understanding of their full range of functions and the details by which they interact with other spindle components. The kinesin-5 (BimC/Eg5) family of motors is largely considered essential to drive spindle pole separation during the initial and latter stages of mitosis. We have deleted the gene encoding the kinesin-5 member in Dictyostelium, (kif13), and find that, in sharp contrast with results found in vertebrate, fly, and yeast organisms, kif13(-) cells continue to grow at rates indistinguishable from wild type. Phenotype analysis reveals a slight increase in spindle elongation rates in the absence of Kif13. More importantly, there is a dramatic, premature separation of spindle halves in kif13(-) cells, suggesting a novel role of this motor in maintaining spindle integrity at the terminal stages of division.
...
PMID:Kinesin-5 is not essential for mitotic spindle elongation in Dictyostelium. 1871 89

Mitotic kinesin Eg5 is a homotetrameric molecular motor that cross-links and slides microtubules. The extent to which Eg5 moves processively is not clear. Here we use three-dimensional tracking of a quantum dot attached to the microtubule in a motility assay to directly visualize the corkscrew motion of a sliding microtubule. We show that the rotational pitch of microtubule sliding conveniently reports on the processivity of the driving motors, confirming that two-headed Eg5 is much less processive than two-headed kinesin-1.
...
PMID:A torque component present in mitotic kinesin Eg5 revealed by three-dimensional tracking. 1880 99

Eg5 is a motor protein of the kinesin family that is critical for spindle assembly during mitosis and has recently been implicated in tumorigenesis. It is largely unknown how Eg5 expression is regulated in cells. In this study, we present the first evidence that the cellular Eg5 level is down-regulated by Parkin, an E3 ubiquitin ligase well known for its role in the development of Parkinson disease. Our data show that Parkin does not trigger Eg5 protein degradation through the ubiquitin-proteasome pathway. Instead, Parkin represses Eg5 gene transcription by blocking c-Jun binding to the activator protein 1 site present in the Eg5 promoter. Our data further show that Parkin inactivates c-Jun NH2-terminal kinase (JNK), resulting in decreased phosphorylation of c-Jun. The inactivation of JNK is further mediated by multiple monoubiquitination of Hsp70. Importantly, both the ubiquitination of Hsp70 and the subsequent inactivation of the JNK-c-Jun pathway are crucial for Parkin to down-regulate Eg5 expression. These results thus uncover a novel function for Parkin in modulating the expression of Eg5 through the Hsp70-JNK-c-Jun signaling pathway.
...
PMID:Parkin regulates Eg5 expression by Hsp70 ubiquitination-dependent inactivation of c-Jun NH2-terminal kinase. 1884 38

Kinesin spindle protein (KSP/Eg5) is essential for the formation and maintenance of bipolar spindles during mitosis. Inhibition of this protein leads to cell cycle arrest and apoptosis without interfering other microtubule-dependent processes. Therefore, it is a potential target in cancer therapy. Here, a series of tetrahydro-beta-carboline derivatives 5a - k were synthesized as kinesin spindle protein inhibitor. Their structures were confirmed with 1H NMR, ESI-MS and elemental analysis. The synthesized compounds were evaluated for their inhibition of KSP.
...
PMID:[Synthesis and biological evaluation of tetrahydro-beta-carline derivatives]. 1895 75


<< Previous 1 2 3 4 5 6 7 8 9 10

---