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

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

The mammary gland undergoes dramatic functional and metabolic changes during the transition from late pregnancy to lactation. To better understand the molecular events underlying these changes, we analyzed expression profiles of approximately 23,000 gene transcripts in bovine mammary tissue about day 5 before parturition and day 10 after parturition. At the cutoff criteria of the signed fold change >or=2 or <or=-2 and false discovery rate (FDR) <or=0.1, a total of 389 transcripts (1.6%) were significantly differentially expressed at the two stages. Of these transcripts with significant changes, 105 were up-regulated while 284 were down-regulated. Gene ontology analysis showed that the main up-regulated genes were those associated with transport activity (amino acid, glucose, and ion transporters), lipid and carbohydrate metabolism (lipoprotein lipase, acetyl-Coenzyme A synthetases, 6-phosphofructo-2-kinase, etc.), and cell signaling factors (protein p8, Rab18, etc.). The main down-regulated genes were associated with cell cycle and proliferation (cyclins, cell division cycle associated proteins, etc.), DNA replication and chromosome organization (centromere proteins, minichromosome maintenance proteins, histone, etc.), microtubule-based processes (microtubule associated protein tau, kinesin, tubulins, etc.), and protein and RNA degradation (proteasome, proteasome activator, RNA binding motif protein, etc.). The increased expression of glucose transporter GLUT1 mRNA during lactation was verified by quantitative reverse transcription/polymerase chain reactin (PCR) (P < 0.05). GLUT1 protein also increased twofold during lactation (P < 0.05). Furthermore, GLUT1 protein was primarily localized in mammary ductal epithelia and blood vessel endothelia before parturition, but was predominantly localized in the basolateral and apical membranes of mammary alveolar epithelial cells during lactation. Our microarray data provide insight into the molecular events in the mammary gland at the onset of lactation, indicating the up-regulation of genes involved in milk synthesis concomitant with the inhibition of those related to cell proliferation.
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PMID:Onset of lactation in the bovine mammary gland: gene expression profiling indicates a strong inhibition of gene expression in cell proliferation. 1825 88

The present study highlights on the biochemical and immunological analysis of MS-KIF18A in pre-osteogenic MBA-15 cells. The protein distribution in various cellular compartments was demonstrated by imaging and Western blot (WB) analysis. MS-KIF18A interactions with cytoskeletal proteins were confirmed for tubulin and actin. The complex between MS-KIF18A and microtubules (MT) was demonstrated in cellular system for endogenous proteins and also between recombinant proteins in pull down and immunoprecipitation (IP) assays. Multiple assays including metabolic labeling, cell fractionation and IP with anti-MS-KIF18A antibody demonstrated an association with actin that was prominent in the cell cytoplasm. Sub-cellular fractionation identified diverse forms of MS-KIF18A in cytoplasm and membrane/nucleus compartments which are suggested to represent the result of post-transcriptional modifications, such as phosphorylation and glycosylation. These modifications on MS-KIF18A were analyzed by bioinformatics and immunological assays. Furthermore, we studied the role of ubiquitin-proteasome system in the MS-KIF18A degradation. Taken together, the current study sheds light on MS-KIF18A a MT-dependent kinesin and adds insights on the post-translational modifications that potentially control the protein cellular distribution and its co-association with cytoskeletal proteins.
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PMID:New insights on cellular distribution, microtubule interactions and post-translational modifications of MS-KIF18A. 1868 Jan 69

MCAK, a kinesin related motor protein with microtubule depolymerizing activity, is known to play an important role in spindle assembly and correcting errors in mitotic chromosome alignment. Experiments to determine how cellular levels of the protein are regulated demonstrate that MCAK accumulates during cell cycle progression, reaches a maximum at G(2)/M phase, and is rapidly degraded by the proteasome during mitosis. Immunofluorescence microscopy further indicates that MCAK largely disappears from kinetochores and spindle poles at the metaphase to anaphase transition. A phosphorylated form of MCAK appears during mitosis and seems to be preferentially degraded, but degradation does not appear to depend on Aurora B, a kinase reported to be involved in regulating the error correcting activity of the protein. These studies indicate that MCAK activity is limited during the latter stages of mitosis by protein degradation, and argue against a role for the protein in anaphase chromosome movement.
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PMID:Cell cycle dependent degradation of MCAK: evidence against a role in anaphase chromosome movement. 1884

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.
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PMID:Parkin regulates Eg5 expression by Hsp70 ubiquitination-dependent inactivation of c-Jun NH2-terminal kinase. 1884 38

Cells keep their energy balance and avoid oxidative stress by regulating mitochondrial movement, distribution, and clearance. We report here that two Parkinson's disease proteins, the Ser/Thr kinase PINK1 and ubiquitin ligase Parkin, participate in this regulation by arresting mitochondrial movement. PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. Removal of Miro from the mitochondrion also detaches kinesin from its surface. By preventing mitochondrial movement, the PINK1/Parkin pathway may quarantine damaged mitochondria prior to their clearance. PINK1 has been shown to act upstream of Parkin, but the mechanism corresponding to this relationship has not been known. We propose that PINK1 phosphorylation of substrates triggers the subsequent action of Parkin and the proteasome.
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PMID:PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. 2251 3

Telomere shortening and disruption of telomeric components are pathways that induce telomere deprotection. Here we describe another pathway, in which prolonged mitotic arrest induces damage signals at telomeres in human cells. Exposure to microtubule drugs, kinesin inhibitors, proteasome inhibitors or the disruption of proper chromosome cohesion resulted in the formation of damage foci at telomeres. Induction of mitotic telomere deprotection coincided with dissociation of TRF2 from telomeres, telomeric 3'-overhang degradation and ATM activation, and deprotection could be suppressed by TRF2 overexpression or inhibition of Aurora B kinase. Normal cells that escaped from prolonged mitotic arrest halted in the following G1 phase, whereas cells lacking p53 continued to cycle and became aneuploid. We propose a telomere-dependent mitotic-duration monitoring system that reacts to improper progression through mitosis.
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PMID:A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest. 2240 14

Kif26b, a member of the kinesin superfamily proteins (KIFs), is essential for kidney development. Kif26b expression is restricted to the metanephric mesenchyme, and its transcription is regulated by a zinc finger transcriptional regulator Sall1. However, the mechanism(s) by which Kif26b protein is regulated remain unknown. Here, we demonstrate phosphorylation and subsequent polyubiquitination of Kif26b in the developing kidney. We find that Kif26b interacts with an E3 ubiquitin ligase, neural precursor cell expressed developmentally down-regulated protein 4 (Nedd4) in developing kidney. Phosphorylation of Kif26b at Thr-1859 and Ser-1962 by the cyclin-dependent kinases (CDKs) enhances the interaction of Kif26b with Nedd4. Nedd4 polyubiquitinates Kif26b and thereby promotes degradation of Kif26b via the ubiquitin-proteasome pathway. Furthermore, Kif26b lacks ATPase activity but does associate with microtubules. Nocodazole treatment not only disrupts the localization of Kif26b to microtubules but also promotes phosphorylation and polyubiquitination of Kif26b. These results suggest that the function of Kif26b is microtubule-based and that Kif26b degradation in the metanephric mesenchyme via the ubiquitin-proteasome pathway may be important for proper kidney development.
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PMID:Phosphorylation of Kif26b promotes its polyubiquitination and subsequent proteasomal degradation during kidney development. 2276 11

Kinesin-like calmodulin binding protein (KCBP) is a member of kinesin-14 subfamily with unconventional domains distinct from other kinesins. This unique kinesin has the myosin tail homology 4 domain (MyTH4) and band4.1, ezrin, radixin and moesin domain (FERM) at the N-terminal which interact with several cytoskeleton proteins. Although KCBP is implicated in several microtubule-related cellular processes, studies on the KCBP of Dunaliella salina (DsKCBP) have not been reported. In this study, the roles of DsKCBP in flagella and cytoskeleton were investigated and the results showed that DsKCBP was present in flagella and upregulated during flagellar assembly indicting that it may be a flagellar kinesin and plays a role in flagellar assembly. A MyTH4-FERM domain of the DsKCBP was identified as a microtubule and actin interacting site. The interaction of DsKCBP with both microtubules and actin microfilaments suggests that this kinesin may be employed to coordinate these two cytoskeleton elements in algal cells. To gain more insights into the cellular function of the kinesin, DsKCBP-interacting proteins were examined using yeast two-hybrid screen. A 26S proteasome subunit Rpn8 was identified as a novel interacting partner of DsKCBP and the MyTH4-FERM domain was necessary for the interaction of DsKCBP with Rpn8. Furthermore, the DsKCBP was polyubiquitinated and up-regulated by proteasome inhibitor and degraded by ubiquitin-proteasome system indicating that proteasome is related to kinesin degradation.
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PMID:The degradation of kinesin-like calmodulin binding protein of D. salina (DsKCBP) is mediated by the ubiquitin-proteasome system. 2327 Nov 17

Multiple myeloma (MM) refractory to both proteasome inhibitors and immunomodulatory agents (IMiDs; double-refractory myeloma) has a poor prognosis. With the more frequent use of these agents as part of initial therapy, and then in the maintenance setting until disease progression, such drug resistance is an emerging problem of great significance. New therapeutic strategies are clearly needed for this patient population, including the development of more potent agents within existing antimyeloma drug classes, exploration of rational combinations of both novel and conventional drugs, and validation of new myeloma drug targets. Several approaches have shown substantial promise, including use of the second-generation proteasome inhibitor carfilzomib and the third-generation IMiD pomalidomide, which led to the recent regulatory approval of both agents. In addition, the kinesin-spindle protein KSP inhibitor ARRY-520 has shown activity as a first-in-class drug in myeloma therapeutics, whereas the histone deacetylase (HDAC) inhibitors vorinostat and panobinostat have demonstrated efficacy when used in rational combinations. This overview provides a summary of novel agents that have shown activity in double-refractory myeloma in recent phase II and III clinical trials, and a framework for future studies that will help to improve outcomes in this patient population.
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PMID:Novel approaches to treatment of double-refractory multiple myeloma. 2371 30

Treatment in medical oncology is gradually shifting from the use of nonspecific chemotherapeutic agents toward an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second- and third-generation proteasome inhibitors (PIs), immunomodulatory agents and alkylators). Next, we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAbs), cell cycle-specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors and kinase inhibitors. Among this plethora of new agents or mechanisms, some are specially promising: anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Moreover, the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, which has produced exciting results in the relapsed/refractory setting.
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PMID:New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG). 2425 22


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