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Rbbp4 loss disrupts neural progenitor cell cycle regulation independent of Rb and leads to Tp53 acetylation and apoptosis

BACKGROUND: Retinoblastoma binding protein 4 (Rbbp4) is a component of transcription regulatory complexes that control cell cycle gene expression. Previous work indicated that Rbbp4 cooperates with the Rb tumor suppressor to block cell cycle entry. Here, we use genetic analysis to examine the intera...

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Autores principales: Schultz‐Rogers, Laura E., Thayer, Michelle L., Kambakam, Sekhar, Wierson, Wesley A., Helmer, Jordan A., Wishman, Mark D., Wall, Kristen A., Greig, Jessica L., Forsman, Jaimie L., Puchhalapalli, Kavya, Nair, Siddharth, Weiss, Trevor J., Luiken, Jon M., Blackburn, Patrick R., Ekker, Stephen C., Kool, Marcel, McGrail, Maura
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9356990/
https://www.ncbi.nlm.nih.gov/pubmed/35266256
http://dx.doi.org/10.1002/dvdy.467
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author Schultz‐Rogers, Laura E.
Thayer, Michelle L.
Kambakam, Sekhar
Wierson, Wesley A.
Helmer, Jordan A.
Wishman, Mark D.
Wall, Kristen A.
Greig, Jessica L.
Forsman, Jaimie L.
Puchhalapalli, Kavya
Nair, Siddharth
Weiss, Trevor J.
Luiken, Jon M.
Blackburn, Patrick R.
Ekker, Stephen C.
Kool, Marcel
McGrail, Maura
author_facet Schultz‐Rogers, Laura E.
Thayer, Michelle L.
Kambakam, Sekhar
Wierson, Wesley A.
Helmer, Jordan A.
Wishman, Mark D.
Wall, Kristen A.
Greig, Jessica L.
Forsman, Jaimie L.
Puchhalapalli, Kavya
Nair, Siddharth
Weiss, Trevor J.
Luiken, Jon M.
Blackburn, Patrick R.
Ekker, Stephen C.
Kool, Marcel
McGrail, Maura
author_sort Schultz‐Rogers, Laura E.
collection PubMed
description BACKGROUND: Retinoblastoma binding protein 4 (Rbbp4) is a component of transcription regulatory complexes that control cell cycle gene expression. Previous work indicated that Rbbp4 cooperates with the Rb tumor suppressor to block cell cycle entry. Here, we use genetic analysis to examine the interactions of Rbbp4, Rb, and Tp53 in zebrafish neural progenitor cell cycle regulation and survival. RESULTS: Rbbp4 is upregulated across the spectrum of human embryonal and glial brain cancers. Transgenic rescue of rbbp4 mutant embryos shows Rbbp4 is essential for zebrafish neurogenesis. Rbbp4 loss leads to apoptosis and γ‐H2AX in the developing brain that is suppressed by tp53 knockdown or maternal zygotic deletion. Mutant retinal neural precursors accumulate in M phase and fail to initiate G0 gene expression. rbbp4; rb1 mutants show an additive effect on the number of M phase cells. In rbbp4 mutants, Tp53 acetylation is detected; however, Rbbp4 overexpression did not rescue DNA damage‐induced apoptosis. CONCLUSION: Rbbp4 is necessary for neural progenitor cell cycle progression and initiation of G0 independent of Rb. Tp53‐dependent apoptosis in the absence of Rbpb4 correlates with Tp53 acetylation. Together these results suggest that Rbbp4 is required for cell cycle exit and contributes to neural progenitor survival through the regulation of Tp53 acetylation.
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spelling pubmed-93569902022-10-14 Rbbp4 loss disrupts neural progenitor cell cycle regulation independent of Rb and leads to Tp53 acetylation and apoptosis Schultz‐Rogers, Laura E. Thayer, Michelle L. Kambakam, Sekhar Wierson, Wesley A. Helmer, Jordan A. Wishman, Mark D. Wall, Kristen A. Greig, Jessica L. Forsman, Jaimie L. Puchhalapalli, Kavya Nair, Siddharth Weiss, Trevor J. Luiken, Jon M. Blackburn, Patrick R. Ekker, Stephen C. Kool, Marcel McGrail, Maura Dev Dyn Research Articles BACKGROUND: Retinoblastoma binding protein 4 (Rbbp4) is a component of transcription regulatory complexes that control cell cycle gene expression. Previous work indicated that Rbbp4 cooperates with the Rb tumor suppressor to block cell cycle entry. Here, we use genetic analysis to examine the interactions of Rbbp4, Rb, and Tp53 in zebrafish neural progenitor cell cycle regulation and survival. RESULTS: Rbbp4 is upregulated across the spectrum of human embryonal and glial brain cancers. Transgenic rescue of rbbp4 mutant embryos shows Rbbp4 is essential for zebrafish neurogenesis. Rbbp4 loss leads to apoptosis and γ‐H2AX in the developing brain that is suppressed by tp53 knockdown or maternal zygotic deletion. Mutant retinal neural precursors accumulate in M phase and fail to initiate G0 gene expression. rbbp4; rb1 mutants show an additive effect on the number of M phase cells. In rbbp4 mutants, Tp53 acetylation is detected; however, Rbbp4 overexpression did not rescue DNA damage‐induced apoptosis. CONCLUSION: Rbbp4 is necessary for neural progenitor cell cycle progression and initiation of G0 independent of Rb. Tp53‐dependent apoptosis in the absence of Rbpb4 correlates with Tp53 acetylation. Together these results suggest that Rbbp4 is required for cell cycle exit and contributes to neural progenitor survival through the regulation of Tp53 acetylation. John Wiley & Sons, Inc. 2022-03-18 2022-08 /pmc/articles/PMC9356990/ /pubmed/35266256 http://dx.doi.org/10.1002/dvdy.467 Text en © 2022 The Authors. Developmental Dynamics published by Wiley Periodicals LLC on behalf of American Association for Anatomy. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Schultz‐Rogers, Laura E.
Thayer, Michelle L.
Kambakam, Sekhar
Wierson, Wesley A.
Helmer, Jordan A.
Wishman, Mark D.
Wall, Kristen A.
Greig, Jessica L.
Forsman, Jaimie L.
Puchhalapalli, Kavya
Nair, Siddharth
Weiss, Trevor J.
Luiken, Jon M.
Blackburn, Patrick R.
Ekker, Stephen C.
Kool, Marcel
McGrail, Maura
Rbbp4 loss disrupts neural progenitor cell cycle regulation independent of Rb and leads to Tp53 acetylation and apoptosis
title Rbbp4 loss disrupts neural progenitor cell cycle regulation independent of Rb and leads to Tp53 acetylation and apoptosis
title_full Rbbp4 loss disrupts neural progenitor cell cycle regulation independent of Rb and leads to Tp53 acetylation and apoptosis
title_fullStr Rbbp4 loss disrupts neural progenitor cell cycle regulation independent of Rb and leads to Tp53 acetylation and apoptosis
title_full_unstemmed Rbbp4 loss disrupts neural progenitor cell cycle regulation independent of Rb and leads to Tp53 acetylation and apoptosis
title_short Rbbp4 loss disrupts neural progenitor cell cycle regulation independent of Rb and leads to Tp53 acetylation and apoptosis
title_sort rbbp4 loss disrupts neural progenitor cell cycle regulation independent of rb and leads to tp53 acetylation and apoptosis
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9356990/
https://www.ncbi.nlm.nih.gov/pubmed/35266256
http://dx.doi.org/10.1002/dvdy.467
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