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)

Many forms of intracellular transport are mediated by microtubule-dependent motors of the kinesin superfamily (KIFs). To identify kinesins expressed in human retina and RPE, we used degenerate primer RT-PCR to amplify a approximately 440 bp kinesin motor domain fragment from human retinal and RPE messenger RNAs. Four distinct kinesins were detected: one C-kinesin (HsKIFC3); one kinesin from the unc104/KIF1 family [HsKIF1A]; and the ubiquitous and neuronal forms of conventional kinesin heavy chain [HsuKHC and HsnKHC]. The C-kinesin HsKIFC3 comprised 33.3% of the retinal clones and was 60% identical to FKIF2, the most abundant kinesin detected in a previous screen of fish retina and 95% identical to a fragment of MmKifC3 recently amplified from mouse brain. Elsewhere we have reported the sequence of HsKIFC3 and shown that it maps to the same locus on chromosome 16q13-q21 as Bardet-Biedl syndrome Type II, a hereditary retinal degeneration. We describe here the kinesin PCR screen of human retina and RPE and examine the tissue and subcellular distribution of KIFC3 in both fish and human retina using an antibody raised against a peptide conserved between FKIF2 and HsKIFC3. This peptide antibody identified a single approximately 80 kDa band in Western blots of fish and human retina and RPE. In both fish and human retina this antibody strongly labeled photoreceptor terminals in the outer plexiform layer, suggesting that FKIF2/KIFC3 may play some role in the photoreceptor synapse.
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PMID:Characterization of a novel C-kinesin (KIFC3) abundantly expressed in vertebrate retina and RPE. 1037 49

The persistent malattachment of microtubules to chromosomes at kinetochores is a major mechanism of chromosomal instability (CIN) [1, 2]. In normal diploid cells, malattachments arise spontaneously and are efficiently corrected to preserve genomic stability [3]. However, it is unknown whether cancer cells with CIN possess the ability to efficiently correct attachment errors. Here we show that kinetochore microtubule attachments in cancer cells with CIN are inherently more stable than those in normal diploid RPE-1 cells. The observed differences in attachment stability account for the persistence of malattachments into anaphase, where they cause chromosome missegregation. Furthermore, increasing the stability of kinetochore microtubule attachments in normal diploid RPE-1 cells, either by depleting the tumor suppressor protein APC or the kinesin-13 protein MCAK, is sufficient to promote chromosome segregation defects to levels comparable to those in cancer cells with CIN. Collectively, these data identify that cancer cells have a diminished capacity to correct erroneous kinetochore microtubule attachments and account for the widespread occurrence of CIN in tumors [4].
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PMID:Deviant kinetochore microtubule dynamics underlie chromosomal instability. 1994 39

During mitosis, equal segregation of chromosomes depends on proper kinetochore-microtubule attachments. Merotelic kinetochore orientation, in which a single kinetochore binds microtubules from both spindle poles [1], is a major cause of chromosome instability [2], which is commonly observed in solid tumors [3, 4]. Using the fission yeast Schizosaccharomyces pombe, we show that a proper force balance between kinesin motors on interpolar spindle microtubules is critical for correcting merotelic attachments. Inhibition of the plus-end-directed spindle elongation motors kinesin-5 (Cut7) and kinesin-6 (Klp9) reduces spindle length, tension at kinetochores, and the frequency of merotelic attachments. In contrast, merotely is increased by deletion of the minus-end-directed kinesin-14 (Klp2) or overexpression of Klp9. Also, Cdk1 regulates spindle elongation forces to promote merotelic correction by phosphorylating and inhibiting Klp9. The role of spindle elongation motors in merotelic correction is conserved, because partial inhibition of the human kinesin-5 homolog Eg5 using the drug monastrol reduces spindle length and lagging chromosome frequency in both normal (RPE-1) and tumor (CaCo-2) cells. These findings reveal unexpected links between spindle forces and correction of merotelic attachments and show that pharmacological manipulation of spindle elongation forces might be used to reduce chromosome instability in cancer cells.
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PMID:A role for metaphase spindle elongation forces in correction of merotelic kinetochore attachments. 2226 9

Cell proliferation is driven by cyclical activation of cyclin-dependent kinases (CDKs), which produce distinct biochemical cell cycle phases. Mitosis (M phase) is orchestrated by CDK-1, complexed with mitotic cyclins. During M phase, chromosomes are segregated by a bipolar array of microtubules called the mitotic spindle. The essential bipolarity of the mitotic spindle is established by the kinesin-5 Eg5, but factors influencing the maintenance of spindle bipolarity are not fully understood. Here, we describe an unexpected link between inhibiting CDK-1 before mitosis and bipolar spindle maintenance. Spindles in human RPE-1 cells normally collapse to monopolar structures when Eg5 is inhibited at metaphase. However, we found that inhibition of CDK-1 in the G2 phase of the cell cycle improved the ability of RPE-1 cells to maintain spindle bipolarity without Eg5 activity in the mitosis immediately after release from CDK-1 inhibition. This improved bipolarity maintenance correlated with an increase in the stability of kinetochore-microtubules, the subset of microtubules that link chromosomes to the spindle. The improvement in bipolarity maintenance after CDK-1 inhibition in G2 required both the kinesin-12 Kif15 and increased stability of kinetochore-microtubules. Consistent with increased kinetochore-microtubule stability, we find that inhibition of CDK-1 in G2 impairs mitotic fidelity by increasing the incidence of lagging chromosomes in anaphase. These results suggest that inhibition of CDK-1 in G2 causes unpredicted effects in mitosis, even after CDK-1 inhibition is relieved.
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PMID:CDK-1 Inhibition in G2 Stabilizes Kinetochore-Microtubules in the following Mitosis. 2728 42

To uncover their contrasting mechanisms, antimitotic drugs that inhibit Eg5 (kinesin-5) were analyzed in mixed-motor gliding assays of kinesin-1 and Eg5 motors in which Eg5 "braking" dominates motility. Loop-5 inhibitors (monastrol, STLC, ispinesib, and filanesib) increased gliding speeds, consistent with inducing a weak-binding state in Eg5, whereas BRD9876 slowed gliding, consistent with locking Eg5 in a rigor state. Biochemical and single-molecule assays demonstrated that BRD9876 acts as an ATP- and ADP-competitive inhibitor with 4 nM KI. Consistent with its microtubule polymerase activity, Eg5 was shown to stabilize microtubules against depolymerization. This stabilization activity was eliminated in monastrol but was enhanced by BRD9876. Finally, in metaphase-arrested RPE-1 cells, STLC promoted spindle collapse, whereas BRD9876 did not. Thus, different Eg5 inhibitors impact spindle assembly and architecture through contrasting mechanisms, and rigor inhibitors may paradoxically have the capacity to stabilize microtubule arrays in cells.
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PMID:Eg5 Inhibitors Have Contrasting Effects on Microtubule Stability and Metaphase Spindle Integrity. 2816 99