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Evidence for Autoregulation and Cell Signaling Pathway Regulation From Genome-Wide Binding of the Drosophila Retinoblastoma Protein

The retinoblastoma (RB) tumor suppressor protein is a transcriptional cofactor with essential roles in cell cycle and development. Physical and functional targets of RB and its paralogs p107/p130 have been studied largely in cultured cells, but the full biological context of this family of proteins’...

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Autores principales: Acharya, Pankaj, Negre, Nicolas, Johnston, John, Wei, Yiliang, White, Kevin P., Henry, R. William, Arnosti, David N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Genetics Society of America 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3484676/
https://www.ncbi.nlm.nih.gov/pubmed/23173097
http://dx.doi.org/10.1534/g3.112.004424
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author Acharya, Pankaj
Negre, Nicolas
Johnston, John
Wei, Yiliang
White, Kevin P.
Henry, R. William
Arnosti, David N.
author_facet Acharya, Pankaj
Negre, Nicolas
Johnston, John
Wei, Yiliang
White, Kevin P.
Henry, R. William
Arnosti, David N.
author_sort Acharya, Pankaj
collection PubMed
description The retinoblastoma (RB) tumor suppressor protein is a transcriptional cofactor with essential roles in cell cycle and development. Physical and functional targets of RB and its paralogs p107/p130 have been studied largely in cultured cells, but the full biological context of this family of proteins’ activities will likely be revealed only in whole organismal studies. To identify direct targets of the major Drosophila RB counterpart in a developmental context, we carried out ChIP-Seq analysis of Rbf1 in the embryo. The association of the protein with promoters is developmentally controlled; early promoter access is globally inhibited, whereas later in development Rbf1 is found to associate with promoter-proximal regions of approximately 2000 genes. In addition to conserved cell-cycle–related genes, a wholly unexpected finding was that Rbf1 targets many components of the insulin, Hippo, JAK/STAT, Notch, and other conserved signaling pathways. Rbf1 may thus directly affect output of these essential growth-control and differentiation pathways by regulation of expression of receptors, kinases and downstream effectors. Rbf1 was also found to target multiple levels of its own regulatory hierarchy. Bioinformatic analysis indicates that different classes of genes exhibit distinct constellations of motifs associated with the Rbf1-bound regions, suggesting that the context of Rbf1 recruitment may vary within the Rbf1 regulon. Many of these targeted genes are bound by Rbf1 homologs in human cells, indicating that a conserved role of RB proteins may be to adjust the set point of interlinked signaling networks essential for growth and development.
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spelling pubmed-34846762012-11-21 Evidence for Autoregulation and Cell Signaling Pathway Regulation From Genome-Wide Binding of the Drosophila Retinoblastoma Protein Acharya, Pankaj Negre, Nicolas Johnston, John Wei, Yiliang White, Kevin P. Henry, R. William Arnosti, David N. G3 (Bethesda) Investigations The retinoblastoma (RB) tumor suppressor protein is a transcriptional cofactor with essential roles in cell cycle and development. Physical and functional targets of RB and its paralogs p107/p130 have been studied largely in cultured cells, but the full biological context of this family of proteins’ activities will likely be revealed only in whole organismal studies. To identify direct targets of the major Drosophila RB counterpart in a developmental context, we carried out ChIP-Seq analysis of Rbf1 in the embryo. The association of the protein with promoters is developmentally controlled; early promoter access is globally inhibited, whereas later in development Rbf1 is found to associate with promoter-proximal regions of approximately 2000 genes. In addition to conserved cell-cycle–related genes, a wholly unexpected finding was that Rbf1 targets many components of the insulin, Hippo, JAK/STAT, Notch, and other conserved signaling pathways. Rbf1 may thus directly affect output of these essential growth-control and differentiation pathways by regulation of expression of receptors, kinases and downstream effectors. Rbf1 was also found to target multiple levels of its own regulatory hierarchy. Bioinformatic analysis indicates that different classes of genes exhibit distinct constellations of motifs associated with the Rbf1-bound regions, suggesting that the context of Rbf1 recruitment may vary within the Rbf1 regulon. Many of these targeted genes are bound by Rbf1 homologs in human cells, indicating that a conserved role of RB proteins may be to adjust the set point of interlinked signaling networks essential for growth and development. Genetics Society of America 2012-11-01 /pmc/articles/PMC3484676/ /pubmed/23173097 http://dx.doi.org/10.1534/g3.112.004424 Text en Copyright © 2012 Acharya et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Unported License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Investigations
Acharya, Pankaj
Negre, Nicolas
Johnston, John
Wei, Yiliang
White, Kevin P.
Henry, R. William
Arnosti, David N.
Evidence for Autoregulation and Cell Signaling Pathway Regulation From Genome-Wide Binding of the Drosophila Retinoblastoma Protein
title Evidence for Autoregulation and Cell Signaling Pathway Regulation From Genome-Wide Binding of the Drosophila Retinoblastoma Protein
title_full Evidence for Autoregulation and Cell Signaling Pathway Regulation From Genome-Wide Binding of the Drosophila Retinoblastoma Protein
title_fullStr Evidence for Autoregulation and Cell Signaling Pathway Regulation From Genome-Wide Binding of the Drosophila Retinoblastoma Protein
title_full_unstemmed Evidence for Autoregulation and Cell Signaling Pathway Regulation From Genome-Wide Binding of the Drosophila Retinoblastoma Protein
title_short Evidence for Autoregulation and Cell Signaling Pathway Regulation From Genome-Wide Binding of the Drosophila Retinoblastoma Protein
title_sort evidence for autoregulation and cell signaling pathway regulation from genome-wide binding of the drosophila retinoblastoma protein
topic Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3484676/
https://www.ncbi.nlm.nih.gov/pubmed/23173097
http://dx.doi.org/10.1534/g3.112.004424
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