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Influence of Hsp90 and HDAC inhibition and tubulin acetylation on perinuclear protein aggregation in human retinal pigment epithelial cells.

Ryhänen T, Viiri J, Hyttinen JM, Uusitalo H, Salminen A, Kaarniranta K - J. Biomed. Biotechnol. (2010)

Bottom Line: We demonstrate that Hsp90 inhibition by geldanamycin can effectively suppress proteasome inhibitor, MG-132-induced protein aggregation in a way that is independent of HDAC inhibition or the tubulin acetylation levels in ARPE-19 cells.However, the tubulin acetylation and polymerization state affects the localization of the proteasome-inhibitor-induced aggregation.These findings open new perspectives for understanding the pathogenesis of protein aggregation in retinal cells and can be useful for the development of therapeutic treatments to prevent retinal cell deterioration.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, University of Eastern Finland, 70211 Kuopio, Finland.

ABSTRACT
Retinal pigment epithelial (RPE) cells are continually exposed to oxidative stress that contributes to protein misfolding, aggregation and functional abnormalities during aging. The protein aggregates formed at the cell periphery are delivered along the microtubulus network by dynein-dependent retrograde trafficking to a juxtanuclear location. We demonstrate that Hsp90 inhibition by geldanamycin can effectively suppress proteasome inhibitor, MG-132-induced protein aggregation in a way that is independent of HDAC inhibition or the tubulin acetylation levels in ARPE-19 cells. However, the tubulin acetylation and polymerization state affects the localization of the proteasome-inhibitor-induced aggregation. These findings open new perspectives for understanding the pathogenesis of protein aggregation in retinal cells and can be useful for the development of therapeutic treatments to prevent retinal cell deterioration.

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Related in: MedlinePlus

(a) Transmission electron micrographs of control (C) cells, and cells exposed to 5 μM MG-132 (MG) or 0.25 μM geldanamycin (GA) or 1 μM trichostatin A (TSA) or 1 μM taxol (TAX) or 5 μM nocodazole (NOC)  for 24 hours. In addition, the cells were treated simultaneously with GA or TSA or TAX or NOC and MG-132 for up to 24 hours, (b) and then allowed to recover under the indicated conditions for 24 hours.
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fig2: (a) Transmission electron micrographs of control (C) cells, and cells exposed to 5 μM MG-132 (MG) or 0.25 μM geldanamycin (GA) or 1 μM trichostatin A (TSA) or 1 μM taxol (TAX) or 5 μM nocodazole (NOC) for 24 hours. In addition, the cells were treated simultaneously with GA or TSA or TAX or NOC and MG-132 for up to 24 hours, (b) and then allowed to recover under the indicated conditions for 24 hours.

Mentions: The ARPE-19 cells were either nonstressed, or exposed to drugs, that is, 5 μM MG-132 or 0.25 μM geldanamycin, 1 μM trichostatin A or 1 μM taxol or 5 μM nocodazole for 24 hours. In addition, the cells were treated simultaneously with MG-132 in conjunction with geldanamycin, trichosatin A, taxol or nocodazole up to 24 hours. Only a single MG-132 insult or combination treatment with taxol induced a typical perinuclear aggregation in ARPE cells (Figures 1(a) and 2(a)). Interestingly, Hsp90 inhibition with geldanamycin effectively suppressed MG-132 induced protein aggregation. HDAC inhibition with trichostatin A or tubulin depolymerization with nocodazole evoked dispersed the mid-peripherical aggregation process during proteasome inhibition. With all of the insults, cytoplasm underwent a similar effective aggregation clearance when exposed to MG-132 for 24 hours and then allowed to recover for 24 hours in normal cell culture medium (Figures 1(b) and 2(b)).


Influence of Hsp90 and HDAC inhibition and tubulin acetylation on perinuclear protein aggregation in human retinal pigment epithelial cells.

Ryhänen T, Viiri J, Hyttinen JM, Uusitalo H, Salminen A, Kaarniranta K - J. Biomed. Biotechnol. (2010)

(a) Transmission electron micrographs of control (C) cells, and cells exposed to 5 μM MG-132 (MG) or 0.25 μM geldanamycin (GA) or 1 μM trichostatin A (TSA) or 1 μM taxol (TAX) or 5 μM nocodazole (NOC)  for 24 hours. In addition, the cells were treated simultaneously with GA or TSA or TAX or NOC and MG-132 for up to 24 hours, (b) and then allowed to recover under the indicated conditions for 24 hours.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2963810&req=5

fig2: (a) Transmission electron micrographs of control (C) cells, and cells exposed to 5 μM MG-132 (MG) or 0.25 μM geldanamycin (GA) or 1 μM trichostatin A (TSA) or 1 μM taxol (TAX) or 5 μM nocodazole (NOC) for 24 hours. In addition, the cells were treated simultaneously with GA or TSA or TAX or NOC and MG-132 for up to 24 hours, (b) and then allowed to recover under the indicated conditions for 24 hours.
Mentions: The ARPE-19 cells were either nonstressed, or exposed to drugs, that is, 5 μM MG-132 or 0.25 μM geldanamycin, 1 μM trichostatin A or 1 μM taxol or 5 μM nocodazole for 24 hours. In addition, the cells were treated simultaneously with MG-132 in conjunction with geldanamycin, trichosatin A, taxol or nocodazole up to 24 hours. Only a single MG-132 insult or combination treatment with taxol induced a typical perinuclear aggregation in ARPE cells (Figures 1(a) and 2(a)). Interestingly, Hsp90 inhibition with geldanamycin effectively suppressed MG-132 induced protein aggregation. HDAC inhibition with trichostatin A or tubulin depolymerization with nocodazole evoked dispersed the mid-peripherical aggregation process during proteasome inhibition. With all of the insults, cytoplasm underwent a similar effective aggregation clearance when exposed to MG-132 for 24 hours and then allowed to recover for 24 hours in normal cell culture medium (Figures 1(b) and 2(b)).

Bottom Line: We demonstrate that Hsp90 inhibition by geldanamycin can effectively suppress proteasome inhibitor, MG-132-induced protein aggregation in a way that is independent of HDAC inhibition or the tubulin acetylation levels in ARPE-19 cells.However, the tubulin acetylation and polymerization state affects the localization of the proteasome-inhibitor-induced aggregation.These findings open new perspectives for understanding the pathogenesis of protein aggregation in retinal cells and can be useful for the development of therapeutic treatments to prevent retinal cell deterioration.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, University of Eastern Finland, 70211 Kuopio, Finland.

ABSTRACT
Retinal pigment epithelial (RPE) cells are continually exposed to oxidative stress that contributes to protein misfolding, aggregation and functional abnormalities during aging. The protein aggregates formed at the cell periphery are delivered along the microtubulus network by dynein-dependent retrograde trafficking to a juxtanuclear location. We demonstrate that Hsp90 inhibition by geldanamycin can effectively suppress proteasome inhibitor, MG-132-induced protein aggregation in a way that is independent of HDAC inhibition or the tubulin acetylation levels in ARPE-19 cells. However, the tubulin acetylation and polymerization state affects the localization of the proteasome-inhibitor-induced aggregation. These findings open new perspectives for understanding the pathogenesis of protein aggregation in retinal cells and can be useful for the development of therapeutic treatments to prevent retinal cell deterioration.

Show MeSH
Related in: MedlinePlus