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Paradoxical Instability–Activity Relationship Defines a Novel Regulatory Pathway for Retinoblastoma Proteins

The Retinoblastoma (RB) transcriptional corepressor and related family of pocket proteins play central roles in cell cycle control and development, and the regulatory networks governed by these factors are frequently inactivated during tumorigenesis. During normal growth, these proteins are subject...

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Autores principales: Acharya, Pankaj, Raj, Nitin, Buckley, Martin S., Zhang, Liang, Duperon, Stephanie, Williams, Geoffrey, Henry, R. William, Arnosti, David N.
Formato: Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2982090/
https://www.ncbi.nlm.nih.gov/pubmed/20861300
http://dx.doi.org/10.1091/mbc.E10-06-0520
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author Acharya, Pankaj
Raj, Nitin
Buckley, Martin S.
Zhang, Liang
Duperon, Stephanie
Williams, Geoffrey
Henry, R. William
Arnosti, David N.
author_facet Acharya, Pankaj
Raj, Nitin
Buckley, Martin S.
Zhang, Liang
Duperon, Stephanie
Williams, Geoffrey
Henry, R. William
Arnosti, David N.
author_sort Acharya, Pankaj
collection PubMed
description The Retinoblastoma (RB) transcriptional corepressor and related family of pocket proteins play central roles in cell cycle control and development, and the regulatory networks governed by these factors are frequently inactivated during tumorigenesis. During normal growth, these proteins are subject to tight control through at least two mechanisms. First, during cell cycle progression, repressor potential is down-regulated by Cdk-dependent phosphorylation, resulting in repressor dissociation from E2F family transcription factors. Second, RB proteins are subject to proteasome-mediated destruction during development. To better understand the mechanism for RB family protein instability, we characterized Rbf1 turnover in Drosophila and the protein motifs required for its destabilization. We show that specific point mutations in a conserved C-terminal instability element strongly stabilize Rbf1, but strikingly, these mutations also cripple repression activity. Rbf1 is destabilized specifically in actively proliferating tissues of the larva, indicating that controlled degradation of Rbf1 is linked to developmental signals. The positive linkage between Rbf1 activity and its destruction indicates that repressor function is governed in a manner similar to that described by the degron theory of transcriptional activation. Analogous mutations in the mammalian RB family member p107 similarly induce abnormal accumulation, indicating substantial conservation of this regulatory pathway.
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spelling pubmed-29820902011-01-30 Paradoxical Instability–Activity Relationship Defines a Novel Regulatory Pathway for Retinoblastoma Proteins Acharya, Pankaj Raj, Nitin Buckley, Martin S. Zhang, Liang Duperon, Stephanie Williams, Geoffrey Henry, R. William Arnosti, David N. Mol Biol Cell Articles The Retinoblastoma (RB) transcriptional corepressor and related family of pocket proteins play central roles in cell cycle control and development, and the regulatory networks governed by these factors are frequently inactivated during tumorigenesis. During normal growth, these proteins are subject to tight control through at least two mechanisms. First, during cell cycle progression, repressor potential is down-regulated by Cdk-dependent phosphorylation, resulting in repressor dissociation from E2F family transcription factors. Second, RB proteins are subject to proteasome-mediated destruction during development. To better understand the mechanism for RB family protein instability, we characterized Rbf1 turnover in Drosophila and the protein motifs required for its destabilization. We show that specific point mutations in a conserved C-terminal instability element strongly stabilize Rbf1, but strikingly, these mutations also cripple repression activity. Rbf1 is destabilized specifically in actively proliferating tissues of the larva, indicating that controlled degradation of Rbf1 is linked to developmental signals. The positive linkage between Rbf1 activity and its destruction indicates that repressor function is governed in a manner similar to that described by the degron theory of transcriptional activation. Analogous mutations in the mammalian RB family member p107 similarly induce abnormal accumulation, indicating substantial conservation of this regulatory pathway. The American Society for Cell Biology 2010-11-15 /pmc/articles/PMC2982090/ /pubmed/20861300 http://dx.doi.org/10.1091/mbc.E10-06-0520 Text en © 2010 by The American Society for Cell Biology 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 (http://creativecommons.org/licenses/by-nc-sa/3.0).
spellingShingle Articles
Acharya, Pankaj
Raj, Nitin
Buckley, Martin S.
Zhang, Liang
Duperon, Stephanie
Williams, Geoffrey
Henry, R. William
Arnosti, David N.
Paradoxical Instability–Activity Relationship Defines a Novel Regulatory Pathway for Retinoblastoma Proteins
title Paradoxical Instability–Activity Relationship Defines a Novel Regulatory Pathway for Retinoblastoma Proteins
title_full Paradoxical Instability–Activity Relationship Defines a Novel Regulatory Pathway for Retinoblastoma Proteins
title_fullStr Paradoxical Instability–Activity Relationship Defines a Novel Regulatory Pathway for Retinoblastoma Proteins
title_full_unstemmed Paradoxical Instability–Activity Relationship Defines a Novel Regulatory Pathway for Retinoblastoma Proteins
title_short Paradoxical Instability–Activity Relationship Defines a Novel Regulatory Pathway for Retinoblastoma Proteins
title_sort paradoxical instability–activity relationship defines a novel regulatory pathway for retinoblastoma proteins
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2982090/
https://www.ncbi.nlm.nih.gov/pubmed/20861300
http://dx.doi.org/10.1091/mbc.E10-06-0520
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