Abstract
The molecular chaperone heat shock protein 90 (Hsp90) is a pivotal cellular regulator involved in the folding, activation and assembly of a wide range of proteins. Hsp90 has multiple roles in the retina and the use of different Hsp90 inhibitors has been shown to prevent retinal degeneration in models of retinitis pigmentosa and age-related macular degeneration. Hsp90 is also a potential target in uveal melanoma. Mechanistically, Hsp90 inhibition can evoke a dual response in the retina; stimulating a stress response with molecular chaperone expression. Thereby leading to an improvement in visual function and photoreceptor survival; however, prolonged inhibition can also stimulate the degradation of Hsp90 client proteins potentially deleteriously affect vision. Here, we review the multiple roles of Hsp90 in the retina and the therapeutic potential of Hsp90 as a target.
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References
Aguila M, Bevilacqua D, McCulley C et al (2014) Hsp90 inhibition protects against inherited retinal degeneration. Hum Mol Genet 23:2164–2175
Athanasiou D, Aguila M, Bevilacqua D et al (2013) The cell stress machinery and retinal degeneration. FEBS Lett 587:2008–2017
Babchia N, Calipel A, Mouriaux F et al (2008) 17-AAG and 17-DMAG-induced inhibition of cell proliferation through B-Raf downregulation in WT B-Raf-expressing uveal melanoma cell lines. Invest Ophthalmol Vis Sci 49:2348–2356
Basso AD, Solit DB, Chiosis G et al (2002) Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function. J Biol Chem 277:39858–39866
Chuang JZ, Vega C, Jun W et al (2004) Structural and functional impairment of endocytic pathways by retinitis pigmentosa mutant rhodopsin-arrestin complexes. J Clin Invest 114:131–140
Dean DO, Tytell M (2001) Hsp25 and -90 immunoreactivity in the normal rat eye. Invest Ophthalmol Vis Sci 42:3031–3040
Decanini A, Nordgaard CL, Feng X et al (2007) Changes in select redox proteins of the retinal pigment epithelium in age-related macular degeneration. Am J Ophthalmol 143:607–615
Egan KM, Seddon JM, Glynn RJ et al (1988) Epidemiologic aspects of uveal melanoma. Surv Ophthalmol 32:239–251
Faingold D, Marshall JC, Antecka E et al (2008) Immune expression and inhibition of heat shock protein 90 in uveal melanoma. Clin Cancer Res 14:847–855
Hess AR, Postovit LM, Margaryan NV et al (2005) Focal adhesion kinase promotes the aggressive melanoma phenotype. Cancer Res 65:9851–9860
Hidalgo-de-Quintana J, Evans RJ, Cheetham ME et al (2008) The Leber congenital amaurosis protein AIPL1 functions as part of a chaperone heterocomplex. Invest Ophthalmol Vis Sci 49:2878–2887
Jarrett SG, Boulton ME (2012) Consequences of oxidative stress in age-related macular degeneration. Mol Aspects Med 33:399–417
Kanamaru C, Yamada Y, Hayashi S et al (2014) Retinal toxicity induced by small-molecule Hsp90 inhibitors in beagle dogs. J Toxicol Sci 39:59–69
Labbadia J, Cunliffe H, Weiss A et al (2011) Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease. J Clin Invest 121:3306–3319
Li J, Buchner J (2013) Structure, function and regulation of the hsp90 machinery. Biomed J 36:106–117
McClellan AJ, Xia Y, Deutschbauer AM et al (2007) Diverse cellular functions of the Hsp90 molecular chaperone uncovered using systems approaches. Cell 131:121–135
Mendes HF, Cheetham ME (2008) Pharmacological manipulation of gain-of-function and dominant-negative mechanisms in rhodopsin retinitis pigmentosa. Hum Mol Genet 17:3043–3054
Neueder A, Achilli F, Moussaoui S et al (2014) Novel isoforms of heat shock transcription factor 1, HSF1gammaalpha and HSF1gammabeta, regulate chaperone protein gene transcription. J Biol Chem 289:19894–19906
Qin S, Ni M, Wang X et al (2011) Inhibition of RPE cell sterile inflammatory responses and endotoxin-induced uveitis by a cell-impermeable HSP90 inhibitor. Exp Eye Res 93:889–897
Rajan A, Kelly RJ, Trepel JB et al (2011) A phase I study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumor malignancies and lymphomas. Clin Cancer Res 17:6831–6839
Saraiva VS, Caissie AL, Segal L et al (2005) Immunohistochemical expression of phospho-Akt in uveal melanoma. Melanoma Res 15:245–250
Sessa C, Shapiro GI, Bhalla KN et al (2013) First-in-human phase I dose-escalation study of the HSP90 inhibitor AUY922 in patients with advanced solid tumors. Clin Cancer Res 19:3671–3680
Tam LC, Kiang AS, Campbell M et al (2010) Prevention of autosomal dominant retinitis pigmentosa by systemic drug therapy targeting heat shock protein 90 (Hsp90). Hum Mol Genet 19:4421–4436
Urbak L, Vorum H (2010) Heat shock proteins in the human eye. International journal of proteomics 2010:479571
Wang YQ, Zhang XM, Wang XD et al (2010) 17-AAG, a Hsp90 inhibitor, attenuates the hypoxia-induced expression of SDF-1alpha and ILK in mouse RPE cells. Mol Biol Rep 37:1203–1209
Wu WC, Kao YH, Hu PS et al (2007) Geldanamycin, a HSP90 inhibitor, attenuates the hypoxia-induced vascular endothelial growth factor expression in retinal pigment epithelium cells in vitro. Exp Eye Res 85:721–731
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This work is supported by the Wellcome Trust and RP Fighting Blindness.
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Aguilà, M., Cheetham, M. (2016). Hsp90 as a Potential Therapeutic Target in Retinal Disease. In: Bowes Rickman, C., LaVail, M., Anderson, R., Grimm, C., Hollyfield, J., Ash, J. (eds) Retinal Degenerative Diseases. Advances in Experimental Medicine and Biology, vol 854. Springer, Cham. https://doi.org/10.1007/978-3-319-17121-0_22
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DOI: https://doi.org/10.1007/978-3-319-17121-0_22
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