Targeting the Kinesin Spindle Protein: Basic Principles and Clinical Implications

Sarli, Vasiliki; Giannis, Athanassios

doi:10.1158/1078-0432.ccr-08-0120

Cited by 130 publications

(115 citation statements)

References 46 publications

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…Cytochalasin D, an inhibitor of actin polymerization that is known to inhibit enucleation, 5 and colchicine, an inhibitor of microtubules that are known to not be directly involved in enucleation 5 (for a review, see Wilson et al 22 ), were purchased from Sigma-Aldrich. Y27632, a well-established inhibitor of ROCK that is a regulator of myosin phosphorylation, 23,24 was purchased from Enzo Life Sciences, Inc. Monastrol, an inhibitor of kinesin Eg5 which is a microtubulebased motor that plays a critical role in mitosis as it mediates centrosome separation and bipolar spindle assembly and maintenance, 25 was from Merck.…”

Section: Cell Division Inhibitorsmentioning

confidence: 99%

Enucleation of human erythroblasts involves non-muscle myosin IIB

Ubukawa

Guo

Takahashi

et al. 2012

Blood

View full text Add to dashboard Cite

Mammalian erythroblasts undergo enucleation, a process thought to be similar to cytokinesis. Although an assemblage of actin, non-muscle myosin II, and several other proteins is crucial for proper cytokinesis, the role of non-muscle myosin II in enucleation remains unclear. In this study, we investigated the effect of various celldivision inhibitors on cytokinesis and enucleation. For this purpose, we used human colony-forming unit-erythroid (CFU-E) and mature erythroblasts generated from purified CD34 ؉ cells as target cells for cytokinesis and enucleation assay, respectively. Here we show that the inhibition of myosin by blebbistatin, an inhibitor of non-muscle myosin II ATPase, blocks both cell division and enucleation, which suggests that non-muscle myosin II plays an essential role not only in cytokinesis but also in enucleation. When the function of non-muscle myosin heavy chain (NMHC) IIA or IIB was inhibited by an exogenous expression of myosin rod fragment, myosin IIA or IIB, each rod fragment blocked the proliferation of CFU-E but only the rod fragment for IIB inhibited the enucleation of mature erythroblasts. These data indicate that NMHC IIB among the isoforms is involved in the enucleation of human erythroblasts. IntroductionDuring erythropoiesis, stem cells undergo lineage specific commitment and generate erythroid progenitor cells through cellular division events including nuclear (mitosis) and cytoplasmic (cytokinesis) division. These progenitor cells consist of immature and mature erythroid progenitors, the burst-forming unit-erythroid (BFU-E) and the colony-forming unit-erythroid (CFU-E), respectively. The BFU-E can be considered as a progenitor of the CFU-E. Indeed, after 6 to 7 days in culture, cells generated from human BFU-E have all the functional characteristics of CFU-E 1 . After an additional 6 to 7 days in culture, human CFU-E proliferate and differentiate into mature erythroblasts. 1 Terminally differentiated erythroblasts in mammals expel their nuclei via a process termed enucleation, becoming reticulocytes and subsequently mature erythrocytes. The nucleus separates from the remainder of the cell and is phagocytosed by reticular cells such as macrophages (for a review, see Chasis et al 2 ).Enucleation of erythroblasts is thought to occur through a process similar to cytokinesis. Several general principles apply to cytokinesis. Firstly, the microtubule cytoskeleton plays an important role in both the choice and positioning of the division site. Once this site is chosen, the local assembly of the actomyosin contractile ring remodels the plasma membrane. Finally, membrane trafficking to, and membrane fusion at the division site result in the physical separation of the daughter cells, a process termed abscission (for reviews, see Barr et al 3 and Glotzer et al 4 ). Although modulation of the actomyosin cytoskeleton is crucial for proper cytokinesis, there is a paucity of information regarding how non-muscle myosin II contributes to enucleation.Several investigations have studied the mol...

show abstract

Section: Cell Division Inhibitorsmentioning

confidence: 99%

Enucleation of human erythroblasts involves non-muscle myosin IIB

Ubukawa

Guo

Takahashi

et al. 2012

Blood

View full text Add to dashboard Cite

show abstract

“…Many of these other proteins are primarily functional only during mitosis and are responsible for controlling different steps in the assembly and function of the complex machinery of the mitotic spindle. Among these proteins, the Aurora kinases (AK), Polo-like kinases (PLK), and kinesin spindle protein (KSP) have emerged as targets for cancer therapeutics (3,4).…”

Section: Introductionmentioning

confidence: 99%

Inhibitors Targeting Mitosis: Tales of How Great Drugs against a Promising Target Were Brought Down by a Flawed Rationale

Komlódi-Pásztor

Sackett

Fojo

2012

Clinical Cancer Research

204

186

View full text Add to dashboard Cite

Although they have been advocated with an understandable enthusiasm, mitosis-specific agents such as inhibitors of mitotic kinases and kinesin spindle protein have not been successful clinically. These drugs were developed as agents that would build on the success of microtubule-targeting agents while avoiding the neurotoxicity that encumbers drugs such as taxanes and vinca alkaloids. The rationale for using mitosisspecific agents was based on the thesis that the clinical efficacy of microtubule-targeting agents could be ascribed to the induction of mitotic arrest. However, the latter concept, which has long been accepted as dogma, is likely important only in cell culture and rapidly growing preclinical models, and irrelevant in patient tumors, where interference with intracellular trafficking on microtubules is likely the principal mechanism of action. Here we review the preclinical and clinical data for a diverse group of inhibitors that target mitosis and identify the reasons why these highly specific, myelosuppressive compounds have failed to deliver on their promise.

show abstract

“…Due toEg5's essential function in mitosis, it is now an important target for the development of inhibitors that have antimitotic activity [7][8][9]. Following the discovery of monastrol [10], the first identified Eg5 inhibitor, a plethora of structurally related and unrelated inhibitors of Eg5 have been recently identified [11][12][13]. Earlier, we have described STLC as an Eg5-specific inhibitor which proved more potent than monastrol [14].…”

Section: Introductionmentioning

confidence: 99%

Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-trityl-l-cysteine in tumor derived cell lines

Tcherniuk

Lis

Kozielski

et al. 2010

Biochemical Pharmacology

View full text Add to dashboard Cite

. Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-Trityl-L-Cysteine in tumor derived cell lines.. Biochemical Pharmacology, Elsevier, 2010, 79 (6) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. confirms the target specificity of monastrol and STLC for Eg5. These data also suggest a possible mechanism by which drug resistance may occur in tumors treated with agents targeting Eg5.

show abstract

Targeting the Kinesin Spindle Protein: Basic Principles and Clinical Implications

Cited by 130 publications

References 46 publications

Enucleation of human erythroblasts involves non-muscle myosin IIB

Enucleation of human erythroblasts involves non-muscle myosin IIB

Inhibitors Targeting Mitosis: Tales of How Great Drugs against a Promising Target Were Brought Down by a Flawed Rationale

Mutations in the human kinesin Eg5 that confer resistance to monastrol and S-trityl-l-cysteine in tumor derived cell lines

Contact Info

Product

Resources

About