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Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration

The ability to sense proteasome insufficiency and respond by directing the transcriptional synthesis of de novo proteasomes is a trait that is conserved in evolution and is found in organisms ranging from yeast to humans. This homeostatic mechanism in mammalian cells is driven by the transcription f...

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Autores principales: Northrop, Amy, Byers, Holly A., Radhakrishnan, Senthil K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550695/
https://www.ncbi.nlm.nih.gov/pubmed/32924844
http://dx.doi.org/10.1091/mbc.E20-04-0238
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author Northrop, Amy
Byers, Holly A.
Radhakrishnan, Senthil K.
author_facet Northrop, Amy
Byers, Holly A.
Radhakrishnan, Senthil K.
author_sort Northrop, Amy
collection PubMed
description The ability to sense proteasome insufficiency and respond by directing the transcriptional synthesis of de novo proteasomes is a trait that is conserved in evolution and is found in organisms ranging from yeast to humans. This homeostatic mechanism in mammalian cells is driven by the transcription factor NRF1. Interestingly, NRF1 is synthesized as an endoplasmic reticulum (ER) membrane protein and when cellular proteasome activity is sufficient, it is retrotranslocated into the cytosol and targeted for destruction by the ER-­associated degradation pathway (ERAD). However, when proteasome capacity is diminished, retrotranslocated NRF1 escapes ERAD and is activated into a mature transcription factor that traverses to the nucleus to induce proteasome genes. In this Perspective, we track the journey of NRF1 from the ER to the nucleus, with a special focus on the various molecular regulators it encounters along its way. Also, using human pathologies such as cancer and neurodegenerative diseases as examples, we explore the notion that modulating the NRF1-proteasome axis could provide the basis for a viable therapeutic strategy in these cases.
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spelling pubmed-75506952020-11-30 Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration Northrop, Amy Byers, Holly A. Radhakrishnan, Senthil K. Mol Biol Cell Perspective The ability to sense proteasome insufficiency and respond by directing the transcriptional synthesis of de novo proteasomes is a trait that is conserved in evolution and is found in organisms ranging from yeast to humans. This homeostatic mechanism in mammalian cells is driven by the transcription factor NRF1. Interestingly, NRF1 is synthesized as an endoplasmic reticulum (ER) membrane protein and when cellular proteasome activity is sufficient, it is retrotranslocated into the cytosol and targeted for destruction by the ER-­associated degradation pathway (ERAD). However, when proteasome capacity is diminished, retrotranslocated NRF1 escapes ERAD and is activated into a mature transcription factor that traverses to the nucleus to induce proteasome genes. In this Perspective, we track the journey of NRF1 from the ER to the nucleus, with a special focus on the various molecular regulators it encounters along its way. Also, using human pathologies such as cancer and neurodegenerative diseases as examples, we explore the notion that modulating the NRF1-proteasome axis could provide the basis for a viable therapeutic strategy in these cases. The American Society for Cell Biology 2020-09-15 /pmc/articles/PMC7550695/ /pubmed/32924844 http://dx.doi.org/10.1091/mbc.E20-04-0238 Text en © 2020 Northrop et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0 This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.
spellingShingle Perspective
Northrop, Amy
Byers, Holly A.
Radhakrishnan, Senthil K.
Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration
title Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration
title_full Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration
title_fullStr Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration
title_full_unstemmed Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration
title_short Regulation of NRF1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration
title_sort regulation of nrf1, a master transcription factor of proteasome genes: implications for cancer and neurodegeneration
topic Perspective
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550695/
https://www.ncbi.nlm.nih.gov/pubmed/32924844
http://dx.doi.org/10.1091/mbc.E20-04-0238
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