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K. Kaarniranta, T. Ryhänen, G. Kalesnykas, M. Niittykoski, K. Vehanen, S. Rönkkö, M. Teräsvirta, A. Salminen, H. Uusitalo; Juxtanuclear Protein Aggregation Is Regulated By Heat Shock Proteins And Microtubulus Acetylation In Human Arpe–19 Cells . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1379.
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Once heat shock protein (Hsp) mediated protein folding fails, the misfolded proteins are tagged with a ubiquitin prior to proteasomal degradation. Protein aggregates formed at the cell periphery are delivered along microtubulus network by retrograde trafficking to a juxtanuclear location. The tubulin undergoes many post–translational modifications, e.g. acetylation what is related to regulation of microtubule stability. Role of Hsp70, Hsp90, proteasome inhibition and microtubulus acetylation were investigated in cellular aggregation in human RPE cells (ARPE–19).
Accumulation of Hsp90, Hsp70, Hsc70, acetylated tubulin and ubiquitinated proteins were analyzed by Western blotting. Microscopy analysis was used to detect cellular organelles in ARPE–19 cells.
Firstly, proteasome inhibitor MG–132 caused robust accumulation of Hsp70 protein and ubiquitinated protein conjugates in ARPE–19 cells. Secondly, Hsp90 inhibitor geldanamycin resulted in a clear protein aggregation that was accompanied by mild acetylation of tubulin. Thirdly, deacetylase inhibitor trichostatin and tubulin stabilizer taxol clearly increased tubulin acetylation and decreased amount of juxtanuclear protein aggregation. In addition, nocodazole, which destabilizes microtubules, caused decreased proteasome inhibitor –induced aggregation. Tubulin acetylation was not affected by nocodazole.
This study reveals that ubiquitin–proteasome pathway is an important way to control protein turnover in the RPE cells. In addition, Hsp90 and Hsp70 and tubulin acetylation are closely related to regulation of the juxtanuclear protein aggregation.
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