Kinesin-5 motor proteins are essential for mitotic spindle formation and maintenance, ensuring accurate chromosome segregation. Human kinesin-5 is highly expressed in various cancer cells but not in nonproliferative tissues; therefore, it is expected to be an attractive target for cancer chemotherapy, with fewer adverse side effects. Many inhibitors have been developed and subjected to clinical trials; however, they have not yet been commercially distributed because of their poor efficacy and frequent drug resistance. Establishing in vivo assay systems to easily monitor inhibitory activity is necessary and valuable to develop more effective inhibitors. Here, we report a procedure to evaluate the inhibitory activity against human kinesin-5 using a fission yeast-based system called "in schizo". Our approach could further be used to screen for inhibitors against kinesin-5 and other human cancer-related targets.
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KIF5A regulates axonal repair and time-dependent axonal transport of SFPQ granules and mitochondria in human motor neurons.
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Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam and VU Medical Center, Amsterdam, the Netherlands; Department of Human Genetics, Amsterdam University Medical Center, Amsterdam, the Netherlands. Electronic address:
Mutations in the microtubule-binding motor protein kinesin 5 A (KIF5A) are implicated in several adult-onset motor neuron diseases, including Amyotrophic Lateral Sclerosis, Spastic Paraplegia Type 10 and Charcot-Marie-Tooth Disease Type 2. While KIF5 family members transport a variety of cargos along axons, the specific cargos affected by KIF5A mutations remain poorly understood. Here, we generated KIF5Anull mutant human motor neurons and analyzed the impact on axonal transport and motor neuron outgrowth and regeneration in vitro.
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Methods Mol Biol
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Laboratory of Molecular and Chemical Cell Biology, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, Japan.
Kinesin-5 motor proteins are essential for mitotic spindle formation and maintenance, ensuring accurate chromosome segregation. Human kinesin-5 is highly expressed in various cancer cells but not in nonproliferative tissues; therefore, it is expected to be an attractive target for cancer chemotherapy, with fewer adverse side effects. Many inhibitors have been developed and subjected to clinical trials; however, they have not yet been commercially distributed because of their poor efficacy and frequent drug resistance.
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Kinesin-5 motors play an essential role during mitotic spindle assembly in many organisms: they crosslink antiparallel spindle microtubules, step toward plus ends, and slide the microtubules apart. This activity separates the spindle poles and chromosomes. Kinesin-5s are not only plus-end-directed but can walk or be carried toward MT minus ends, where they show enhanced localization.
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During neuronal development, neurons undergo significant microtubule reorganization to shape axons and dendrites, establishing the framework for efficient wiring of the nervous system. Previous studies from our laboratory demonstrated the key role of kinesin-1 in driving microtubule-microtubule sliding, which provides the mechanical forces necessary for early axon outgrowth and regeneration in In this study, we reveal the critical role of kinesin-5, a mitotic motor, in modulating the development of postmitotic neurons. Kinesin-5, a conserved homotetrameric motor, typically functions in mitosis by sliding antiparallel microtubules apart in the spindle.
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Laboratory of Molecular Spectroscopy, Department of Organic Chemistry, Faculty of Chemistry, University of Lodz, ul. Tamka 12, 91-403 Łódź, Poland.
Article Synopsis
- Kinesin-5 inhibitors provide a targeted cancer treatment option, reducing harmful side effects commonly associated with other anti-cancer drugs.
- The study focused on modifying the kinesin-5 inhibitor CPUYL064 by adding a ferrocenyl group, creating organometallic hybrids.
- These modified compounds demonstrated significantly improved effectiveness against cancer cells, with some showing up to 19 times greater activity due to the ferrocenyl addition.*
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