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Small Molecule Proteostasis Regulators for Protein Conformational Diseases
Protein homeostasis (proteostasis) is essential for cellular and organismal health. Stress, aging, and the chronic expression of misfolded proteins, however, challenge the proteostasis machinery and the vitality of the cell. Enhanced expression of molecular chaperones, regulated by heat shock transc...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262058/ https://www.ncbi.nlm.nih.gov/pubmed/22198733 http://dx.doi.org/10.1038/nchembio.763 |
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author | Calamini, Barbara Silva, Maria Catarina Madoux, Franck Hutt, Darren M. Khanna, Shilpi Chalfant, Monica A. Saldanha, Sanjay A. Hodder, Peter Tait, Bradley D. Garza, Dan Balch, William E. Morimoto, Richard I. |
author_facet | Calamini, Barbara Silva, Maria Catarina Madoux, Franck Hutt, Darren M. Khanna, Shilpi Chalfant, Monica A. Saldanha, Sanjay A. Hodder, Peter Tait, Bradley D. Garza, Dan Balch, William E. Morimoto, Richard I. |
author_sort | Calamini, Barbara |
collection | PubMed |
description | Protein homeostasis (proteostasis) is essential for cellular and organismal health. Stress, aging, and the chronic expression of misfolded proteins, however, challenge the proteostasis machinery and the vitality of the cell. Enhanced expression of molecular chaperones, regulated by heat shock transcription factor-1 (HSF-1), has been shown to restore proteostasis in a variety of conformational disease models, suggesting a promising therapeutic approach. We describe the results of a ∼900,000 small molecule screen that identified novel classes of small molecule proteostasis regulators (PRs) that induce HSF-1-dependent chaperone expression and restore protein folding in multiple conformational disease models. The beneficial effects to proteome stability are mediated by HSF-1, DAF-16/FOXO, SKN-1/Nrf-2, and the chaperone machinery through mechanisms that are distinct from current known small molecule activators of the HSR. We suggest that modulation of the proteostasis network by PRs represents a promising therapeutic approach for the treatment of a variety of protein conformational diseases. |
format | Online Article Text |
id | pubmed-3262058 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
record_format | MEDLINE/PubMed |
spelling | pubmed-32620582012-08-01 Small Molecule Proteostasis Regulators for Protein Conformational Diseases Calamini, Barbara Silva, Maria Catarina Madoux, Franck Hutt, Darren M. Khanna, Shilpi Chalfant, Monica A. Saldanha, Sanjay A. Hodder, Peter Tait, Bradley D. Garza, Dan Balch, William E. Morimoto, Richard I. Nat Chem Biol Article Protein homeostasis (proteostasis) is essential for cellular and organismal health. Stress, aging, and the chronic expression of misfolded proteins, however, challenge the proteostasis machinery and the vitality of the cell. Enhanced expression of molecular chaperones, regulated by heat shock transcription factor-1 (HSF-1), has been shown to restore proteostasis in a variety of conformational disease models, suggesting a promising therapeutic approach. We describe the results of a ∼900,000 small molecule screen that identified novel classes of small molecule proteostasis regulators (PRs) that induce HSF-1-dependent chaperone expression and restore protein folding in multiple conformational disease models. The beneficial effects to proteome stability are mediated by HSF-1, DAF-16/FOXO, SKN-1/Nrf-2, and the chaperone machinery through mechanisms that are distinct from current known small molecule activators of the HSR. We suggest that modulation of the proteostasis network by PRs represents a promising therapeutic approach for the treatment of a variety of protein conformational diseases. 2011-12-25 /pmc/articles/PMC3262058/ /pubmed/22198733 http://dx.doi.org/10.1038/nchembio.763 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Calamini, Barbara Silva, Maria Catarina Madoux, Franck Hutt, Darren M. Khanna, Shilpi Chalfant, Monica A. Saldanha, Sanjay A. Hodder, Peter Tait, Bradley D. Garza, Dan Balch, William E. Morimoto, Richard I. Small Molecule Proteostasis Regulators for Protein Conformational Diseases |
title | Small Molecule Proteostasis Regulators for Protein Conformational Diseases |
title_full | Small Molecule Proteostasis Regulators for Protein Conformational Diseases |
title_fullStr | Small Molecule Proteostasis Regulators for Protein Conformational Diseases |
title_full_unstemmed | Small Molecule Proteostasis Regulators for Protein Conformational Diseases |
title_short | Small Molecule Proteostasis Regulators for Protein Conformational Diseases |
title_sort | small molecule proteostasis regulators for protein conformational diseases |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262058/ https://www.ncbi.nlm.nih.gov/pubmed/22198733 http://dx.doi.org/10.1038/nchembio.763 |
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