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)

Polycystic kidney disease (PKD) is the most common genetic cause of renal failure in humans. Several proteins that are encoded by genes associated with PKD have recently been identified in primary cilia in renal tubular epithelia. These findings have suggested that abnormalities in cilia formation and function may play a role in the pathogenesis of PKD. To directly determine whether cilia are essential to maintain tubular integrity, we conditionally inactivated KIF3A, a subunit of kinesin-II that is essential for cilia formation, in renal epithelia. Constitutive inactivation of KIF3A produces abnormalities of left-right axis determination and embryonic lethality. Here we show that tissue-specific inactivation of KIF3A in renal tubular epithelial cells results in viable offspring with normal-appearing kidneys at birth. Cysts begin to develop in the kidney at postnatal day 5 and cause renal failure by postnatal day 21. The cyst epithelial cells lack primary cilia and exhibit increased proliferation and apoptosis, apical mislocalization of the epidermal growth factor receptor, increased expression of beta-catenin and c-Myc, and inhibition of p21(CIP1). These results demonstrate that the absence of renal cilia produces both the clinical and cell biological findings associated with PKD. Most generally, the phenotype of Kif3a mutant mice suggests a role for primary cilia in the maintenance of lumen-forming epithelial differentiation.
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PMID:Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. 1273 27

Purine-binding proteins are of critical importance to all living organisms. Approximately 13% of the human genome is devoted to coding for purine-binding proteins. Given their importance, purine-binding proteins are attractive targets for chemotherapeutic intervention against a variety of disease states, particularly cancer. Modern computational and biophysical techniques, combined together in a structure-based drug design approach, aid immensely in the discovery of inhibitors of these targets. This review covers the process of modern structure-based drug design and gives examples of its use in discovery and development of drugs that target purine-binding proteins. The targets reviewed are human purine nucleoside phosphorylase, human epidermal growth factor receptor kinase, and human kinesin spindle protein.
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PMID:Targeting cancer: the challenges and successes of structure-based drug design against the human purinome. 1684 51

The location of proteins that contribute to synaptic function has been widely studied in vertebrate synapses, far more than at model synapses of the genetically manipulable fruit fly, Drosophila melanogaster. Drosophila photoreceptor terminals have been extensively exploited to characterize the actions of synaptic genes, and their distinct and repetitive synaptic ultrastructure is anatomically well suited for such studies. Synaptic release sites include a bipartite T-bar ribbon, comprising a platform surmounting a pedestal. So far, little is known about the composition and precise location of proteins at either the T-bar ribbon or its associated synaptic organelles, knowledge of which is required to understand many details of synaptic function. We studied the localization of candidate proteins to pre- or postsynaptic organelles, by using immuno-electron microscopy with the pre-embedding method, after first validating immunolabeling by confocal microscopy. We used monoclonal antibodies against Bruchpilot, epidermal growth factor receptor pathway substrate clone 15 (EPS-15), and cysteine string protein (CSP), all raised against a fly head homogenate, as well as sea urchin kinesin (antibody SUK4) and Discs large (DLG). All these antibodies labeled distinct synaptic structures in photoreceptor terminals in the first optic neuropil, the lamina, as did rabbit anti-DPAK (Drosophila p21 activated kinase) and anti-Dynamin. Validating reports from light microscopy, immunoreactivity to Bruchpilot localized to the edge of the platform, and immunoreactivity to SUK4 localized to the pedestal of the T-bar ribbon. Anti-DLG recognized the photoreceptor head of capitate projections, invaginating organelles from surrounding glia. For synaptic vesicles, immunoreactivity to EPS-15 localized to sites of endocytosis, and anti-CSP labeled vesicles lying close to the T-bar ribbon. These results provide markers for synaptic sites, and a basis for further functional studies.
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PMID:Immunocytochemical localization of synaptic proteins to photoreceptor synapses of Drosophila melanogaster. 2012 22

Acetylation of microtubules (MT) during endocytosis of epidermal growth factor receptor, c-ErbB1, was studied by confocal immunofluorescence microscopy. It was found that stimulation of endocytosis of c-ErbB1 complexed with the epidermal growth factor (EGF), resulted in continuous raising of MT acetylation that reached its maximum at 60-90 min and then went down to the control level. Simultaneously, the receptor-containing endosomes grew in size and were redistributed into juxtranuclear region. Enlarged endosomes formed dense clusters around MTOC in 60-90 min. Another native c-ErbB1 ligand, transforming growth factor-alpha (TGF-alpha) and unlike EGF causing the receptor recycling, also initiated a wave of MT acetylation, but the effect was expressed more poorly. In this case, endosomes did not grow in size and did not form dense clusters near the MTOC. Cell treatment with deacetylase inhibitor trichostatin A (TSA) caused acetylation of the whole cellular MT population. Under these conditions, translocations of EGF-c-ErbB1-containing endosomes had the same pattern as in the cells untreated with the inhibitor, but the size of endosomes didn't increase during their redistribution into juxtranuclear region. Acetylation was especially pronounced in strongly bent MT regions positioned proximally to MTOC and forming there a dense meshwork whereas peripheral MT plus-ends were basically straight and not modified. We assume that MT acetylation is not so much crucial for preferential interaction with dynein or kinesin and, accordingly, for organization of endosome translocations in a certain direction. It is rather the result of stabilization of some MT pool which supports homotypic fusion of endosomes at early stage of their maturation.
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PMID:[Acetylation of microtubules during endocytosis of epidermal growth factor receptor (c-ErbB1) in interphase HeLa cells]. 2073 5

Timely and accurate assembly of the mitotic spindle is critical for the faithful segregation of chromosomes, and centrosome separation is a key step in this process. The timing of centrosome separation varies dramatically between cell types; however, the mechanisms responsible for these differences and its significance are unclear. Here, we show that activation of epidermal growth factor receptor (EGFR) signaling determines the timing of centrosome separation. Premature separation of centrosomes decreases the requirement for the major mitotic kinesin Eg5 for spindle assembly, accelerates mitosis, and decreases the rate of chromosome missegregation. Importantly, EGF stimulation impacts upon centrosome separation and mitotic progression to different degrees in different cell lines. Cells with high EGFR levels fail to arrest in mitosis upon Eg5 inhibition. This has important implications for cancer therapy because cells with high centrosomal response to EGF are more susceptible to combinatorial inhibition of EGFR and Eg5.
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PMID:EGF-induced centrosome separation promotes mitotic progression and cell survival. 2364 62

Advances in genetic engineering tools have contributed to the development of strategies for utilizing biologically derived vesicles as nanomedicines for achieving cell-specific drug delivery. Here, we describe bioengineered bacterial outer membrane vesicles (OMVs) with low immunogenicity that can target and kill cancer cells in a cell-specific manner by delivering small interfering RNA (siRNA) targeting kinesin spindle protein (KSP). A mutant Escherichia coli strain that exhibits reduced endotoxicity toward human cells was engineered to generate OMVs displaying a human epidermal growth factor receptor 2 (HER2)-specific affibody in the membrane as a targeting ligand. Systemic injection of siRNA-packaged OMVs caused targeted gene silencing and induced highly significant tumor growth regression in an animal model. Importantly, the modified OMVs were well tolerated and showed no evidence of nonspecific side effects. We propose that bioengineered OMVs have great potential as cell-specific drug-delivery vehicles for treating various cancers.
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PMID:Bioengineered bacterial outer membrane vesicles as cell-specific drug-delivery vehicles for cancer therapy. 2441 85

Kinesin-like protein KIFC1, a normally nonessential kinesin motor, plays a critical role in centrosome clustering in cancer cells and is essential for the survival of cancer cells. Herein, we reported that KIFC1 expression is up-regulated in breast cancer, particularly in estrogen receptor negative, progesterone receptor negative and triple negative breast cancer, and is not associated with epidermal growth factor receptor 2 status. In addition, KIFC1 is highly expressed in all 8 tested human breast cancer cell lines, but is absent in normal human mammary epithelial cells and weakly expressed in 2 human lung fibroblast lines. Moreover, KIFC1 silencing significantly reduced breast cancer cell viability. Finally, we found that PJ34, a potent small molecule inhibitor of poly(ADP-ribose) polymerase, suppressed KIFC1 expression and induced multipolar spindle formation in breast cancer cells, and inhibited cell viability and colony formation within the same concentration range, suggesting that KIFC1 suppression by PJ34 contributes to its anti-breast cancer activity. Together, these results suggest that KIFC1 is a novel promising therapeutic target for breast cancer.
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PMID:KIFC1 is a novel potential therapeutic target for breast cancer. 2617 31

Modified polyethyleneimine (PEI) has been widely used as siRNA delivery agents. Here, a new Triton X-100-modified low-molecular-weight PEI siRNA delivery agent is developed together with the coupling of 4-carboxyphenylboronic acid (PBA) and dopamine grafted vitamin E (VEDA). Triton X-100, a nonionic detergent, greatly improves the cellular uptake of siRNA as well as the siRNA escape from endosome/lysosome because of its high transmembrane ability. In addition, the boronate bond between PBA and VEDA of the transfection agent can be triggered to release its entrapped siRNA because of the high level of adenosine triphosphate (ATP) in cancer cells. The transfection agent is successfully applied to deliver siRNAs targeting endogenous genes of epidermal growth factor receptor (EGFR) and kinesin-5 (Eg5) to cancer cells, showing good results on Eg5 and EGFR silencing ability and inhibition of cancer cell migration. Further in vivo study indicates that the Triton X-100-modified transfection agent is also efficient to deliver siRNA to cancer cells and shows significant tumor growth inhibition on mice tumor models. These results indicate that the Triton X-100-modified ATP-responsive transfection agent is a promising gene delivery vector for target gene silencing in vitro and in vivo.
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PMID:Triton X-100-Modified Adenosine Triphosphate-Responsive siRNA Delivery Agent for Antitumor Therapy. 3280 81

Acquired resistance to tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) remains a clinical challenge. Especially challenging are cases in which resistance emerges through EGFR-independent mechanisms, such as through pathways that promote epithelial-to-mesenchymal transition (EMT). Through an integrated transcriptomic, proteomic, and drug screening approach, we identified activation of the yes-associated protein (YAP) and forkhead box protein M1 (FOXM1) axis as a driver of EMT-associated EGFR TKI resistance. EGFR inhibitor resistance was associated with broad multidrug resistance that extended across multiple chemotherapeutic and targeted agents, consistent with the difficulty of effectively treating resistant disease. EGFR TKI-resistant cells displayed increased abundance of spindle assembly checkpoint (SAC) proteins, including polo-like kinase 1 (PLK1), Aurora kinases, survivin, and kinesin spindle protein (KSP). Moreover, EGFR TKI-resistant cells exhibited vulnerability to SAC inhibitors. Increased activation of the YAP/FOXM1 axis mediated an increase in the abundance of SAC components in resistant cells. The clinical relevance of these finding was indicated by evaluation of specimens from patients with EGFR mutant lung cancer, which showed that high FOXM1 expression correlated with expression of genes encoding SAC proteins and was associated with a worse clinical outcome. These data revealed the YAP/FOXM1 axis as a central regulator of EMT-associated EGFR TKI resistance and that this pathway, along with SAC components, are therapeutic vulnerabilities for targeting this multidrug-resistant phenotype.
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PMID:A YAP/FOXM1 axis mediates EMT-associated EGFR inhibitor resistance and increased expression of spindle assembly checkpoint components. 3287 80