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Combined Inactivation of pRB and Hippo Pathways Induces Dedifferentiation in the Drosophila Retina

Functional inactivation of the Retinoblastoma (pRB) pathway is an early and obligatory event in tumorigenesis. The importance of pRB is usually explained by its ability to promote cell cycle exit. Here, we demonstrate that, independently of cell cycle exit control, in cooperation with the Hippo tumo...

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Autores principales: Nicolay, Brandon N., Bayarmagnai, Battuya, Moon, Nam Sung, Benevolenskaya, Elizaveta V., Frolov, Maxim V.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2858677/
https://www.ncbi.nlm.nih.gov/pubmed/20421993
http://dx.doi.org/10.1371/journal.pgen.1000918
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author Nicolay, Brandon N.
Bayarmagnai, Battuya
Moon, Nam Sung
Benevolenskaya, Elizaveta V.
Frolov, Maxim V.
author_facet Nicolay, Brandon N.
Bayarmagnai, Battuya
Moon, Nam Sung
Benevolenskaya, Elizaveta V.
Frolov, Maxim V.
author_sort Nicolay, Brandon N.
collection PubMed
description Functional inactivation of the Retinoblastoma (pRB) pathway is an early and obligatory event in tumorigenesis. The importance of pRB is usually explained by its ability to promote cell cycle exit. Here, we demonstrate that, independently of cell cycle exit control, in cooperation with the Hippo tumor suppressor pathway, pRB functions to maintain the terminally differentiated state. We show that mutations in the Hippo signaling pathway, wts or hpo, trigger widespread dedifferentiation of rbf mutant cells in the Drosophila eye. Initially, rbf wts or rbf hpo double mutant cells are morphologically indistinguishable from their wild-type counterparts as they properly differentiate into photoreceptors, form axonal projections, and express late neuronal markers. However, the double mutant cells cannot maintain their neuronal identity, dedifferentiate, and thus become uncommitted eye specific cells. Surprisingly, this dedifferentiation is fully independent of cell cycle exit defects and occurs even when inappropriate proliferation is fully blocked by a de2f1 mutation. Thus, our results reveal the novel involvement of the pRB pathway during the maintenance of a differentiated state and suggest that terminally differentiated Rb mutant cells are intrinsically prone to dedifferentiation, can be converted to progenitor cells, and thus contribute to cancer advancement.
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spelling pubmed-28586772010-04-26 Combined Inactivation of pRB and Hippo Pathways Induces Dedifferentiation in the Drosophila Retina Nicolay, Brandon N. Bayarmagnai, Battuya Moon, Nam Sung Benevolenskaya, Elizaveta V. Frolov, Maxim V. PLoS Genet Research Article Functional inactivation of the Retinoblastoma (pRB) pathway is an early and obligatory event in tumorigenesis. The importance of pRB is usually explained by its ability to promote cell cycle exit. Here, we demonstrate that, independently of cell cycle exit control, in cooperation with the Hippo tumor suppressor pathway, pRB functions to maintain the terminally differentiated state. We show that mutations in the Hippo signaling pathway, wts or hpo, trigger widespread dedifferentiation of rbf mutant cells in the Drosophila eye. Initially, rbf wts or rbf hpo double mutant cells are morphologically indistinguishable from their wild-type counterparts as they properly differentiate into photoreceptors, form axonal projections, and express late neuronal markers. However, the double mutant cells cannot maintain their neuronal identity, dedifferentiate, and thus become uncommitted eye specific cells. Surprisingly, this dedifferentiation is fully independent of cell cycle exit defects and occurs even when inappropriate proliferation is fully blocked by a de2f1 mutation. Thus, our results reveal the novel involvement of the pRB pathway during the maintenance of a differentiated state and suggest that terminally differentiated Rb mutant cells are intrinsically prone to dedifferentiation, can be converted to progenitor cells, and thus contribute to cancer advancement. Public Library of Science 2010-04-22 /pmc/articles/PMC2858677/ /pubmed/20421993 http://dx.doi.org/10.1371/journal.pgen.1000918 Text en Nicolay et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Nicolay, Brandon N.
Bayarmagnai, Battuya
Moon, Nam Sung
Benevolenskaya, Elizaveta V.
Frolov, Maxim V.
Combined Inactivation of pRB and Hippo Pathways Induces Dedifferentiation in the Drosophila Retina
title Combined Inactivation of pRB and Hippo Pathways Induces Dedifferentiation in the Drosophila Retina
title_full Combined Inactivation of pRB and Hippo Pathways Induces Dedifferentiation in the Drosophila Retina
title_fullStr Combined Inactivation of pRB and Hippo Pathways Induces Dedifferentiation in the Drosophila Retina
title_full_unstemmed Combined Inactivation of pRB and Hippo Pathways Induces Dedifferentiation in the Drosophila Retina
title_short Combined Inactivation of pRB and Hippo Pathways Induces Dedifferentiation in the Drosophila Retina
title_sort combined inactivation of prb and hippo pathways induces dedifferentiation in the drosophila retina
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2858677/
https://www.ncbi.nlm.nih.gov/pubmed/20421993
http://dx.doi.org/10.1371/journal.pgen.1000918
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