TAILIEUCHUNG - Báo cáo khoa học: Adenosine–oligoarginine conjugate, a novel bisubstrate inhibitor, effectively dissociates the actin cytoskeleton

Aberrant regulation of protein kinases impairs normal cellular functioning and may lead to disease. The protein kinase involved in the regulation of the dynamics of the actin cytoskeleton, Rho-kinase (ROCK), phosphory-lates various substrates (. myosin light chain, myosin phosphatase), caus-ing the formation of actin fibers and tension inside cells. | ễFEBS Journal Adenosine-oligoarginine conjugate a novel bisubstrate inhibitor effectively dissociates the actin cytoskeleton Helin Raagel1 2 Marje Lust3 Asko Uri3 and Margus Pooga1 2 1 Institute of Molecular and Cell Biology University of Tartu Estonia 2 Estonian Biocentre Tartu Estonia 3 Institute of Chemistry University of Tartu Estonia Keywords actin cell-penetrating peptide protein kinase inhibitor Rho-kinase Y-27632 Correspondence M. Pooga Estonian Biocentre Riia 23B-226 University of Tartu 51010 Tartu Estonia Fax 3727420286 Tel 3727375024 E-mail mpooga@ Received 11 April2008 revised 8 May 2008 accepted 14 May 2008 doi Aberrant regulation of protein kinases impairs normal cellular functioning and may lead to disease. The protein kinase involved in the regulation of the dynamics of the actin cytoskeleton Rho-kinase ROCK phosphorylates various substrates . myosin light chain myosin phosphatase causing the formation of actin fibers and tension inside cells. Hyperactivation of ROCK for example causes hypertension and cardiovascular disorders. Thus the design of highly specific protein kinase inhibitors is of the utmost importance. To date the majority of inhibitors investigated have been found to mimic and compete with ATP. However in the present study we characterized the cellular effects of a novel bisubstrate inhibitor - adeno-sine-oligoarginine conjugate ARC - designed to interfere simultaneously with the ATP site and the substrate-binding pocket of basophilic kinases. ARC effectively pulled down ROCK from cell lysates showed no cytotoxicity and suppressed the assembly of the actin cytoskeleton especially central actin bundles as the result of interference with the activity of the kinase. Combination of ARC with chloroquine yielded a stronger inhibitory effect and gave results similar to treatment with Y-27632. However treatment with ARC produced more actin fragments and yielded a longer-lasting effect than treatment .

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