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 effects of phenothiazine and carbazole derivatives on the cell-cycle progression of human transformed culture cells were analyzed. After 2 days incubation, 5 microM 1-phenethylamino-3-phenothiazin-10-yl-propan-2-ol (1) induced strong mitotic arrest followed by cell death, and 20 microM 1-(3,6-dichloro-9H-carbazol-9-yl)-3-phenethylamino-2-propanol (5) and 1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenethylamino-2-propanol (6) also induced cell death. The TUNEL-positive nuclei characteristic of apoptotic cell death were detected in cells treated with the compounds. We observed beta- and gamma-tubulins in the arrested cells after the addition of compound 1, and found that more than 90% of the mitotic cells exhibited the monoastral spindle instead of the normal bipolar spindle. The inhibitory effects of compounds 1, 5, and 6 on the microtubule-activated ATPase activity of mitotic kinesin Eg5, which is essential for bipolar spindle formation, were obtained. The most effective inhibitor, compound 1, had an IC(50) of 1.52 microM. We also examined their toxicities on various cell lines. Compound 1 had less toxicity with the non-transformed cell line WI-38, whereas it exhibited strong toxicity with the transformed cell lines WI38VA13, HL-60 and HeLa. On the other hand, a high dose of compound 6 caused cell death in both types of culture cells. These results suggest that compound 1, an Eg5 inhibitor, selectively kills transformed culture cells.
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PMID:Phenothiazine and carbazole-related compounds inhibit mitotic kinesin Eg5 and trigger apoptosis in transformed culture cells. 1681 65

Membrane transport of WAVE2 that leads to lamellipodia formation requires a small GTPase Rac1, the motor protein kinesin, and microtubules. Here we explore the possibility of whether the Rac1-dependent and kinesin-mediated WAVE2 transport along microtubules is regulated by a p21-activated kinase Pak as a downstream effector of Rac1. We find that Pak1 constitutively binds to WAVE2 and is transported with WAVE2 to the leading edge by stimulation with hepatocyte growth factor (HGF). Concomitantly, phosphorylation of tubulin-bound stathmin/Op18 at serine 25 (Ser25) and Ser38, microtubule growth, and stathmin/Op18 binding to kinesin-WAVE2 complex were induced. The HGF-induced WAVE2 transport, lamellipodia formation, stathmin/Op18 phosphorylation at Ser38 and binding to kinesin-WAVE2 complex, but not stathmin/Op18 phosphorylation at Ser25 and microtubule growth, were abrogated by Pak1 inhibitor IPA-3 and Pak1 depletion with small interfering RNA (siRNA). Moreover, stathmin/Op18 depletion with siRNA caused significant inhibition of HGF-induced WAVE2 transport and lamellipodia formation, with HGF-independent promotion of microtubule growth. Collectively, it is suggested that Pak1 plays a critical role in HGF-induced WAVE2 transport and lamellipodia formation by directing Pak1-WAVE2-kinesin complex toward the ends of growing microtubules through phosphorylation and recruitment of tubulin-bound stathmin/Op18 to the complex.
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PMID:Membrane transport of WAVE2 and lamellipodia formation require Pak1 that mediates phosphorylation and recruitment of stathmin/Op18 to Pak1-WAVE2-kinesin complex. 1916 78