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CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability

The CCR4–NOT deadenylase complex plays crucial roles in mRNA decay and translational repression induced by poly(A) tail shortening. Although the in vitro activities of each component of this complex have been well characterized, its in vivo role in immune cells remains unclear. Here we show that mic...

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Autores principales: Inoue, Takeshi, Morita, Masahiro, Hijikata, Atsushi, Fukuda-Yuzawa, Yoko, Adachi, Shungo, Isono, Kyoichi, Ikawa, Tomokatsu, Kawamoto, Hiroshi, Koseki, Haruhiko, Natsume, Tohru, Fukao, Taro, Ohara, Osamu, Yamamoto, Tadashi, Kurosaki, Tomohiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548056/
https://www.ncbi.nlm.nih.gov/pubmed/26238124
http://dx.doi.org/10.1084/jem.20150384
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author Inoue, Takeshi
Morita, Masahiro
Hijikata, Atsushi
Fukuda-Yuzawa, Yoko
Adachi, Shungo
Isono, Kyoichi
Ikawa, Tomokatsu
Kawamoto, Hiroshi
Koseki, Haruhiko
Natsume, Tohru
Fukao, Taro
Ohara, Osamu
Yamamoto, Tadashi
Kurosaki, Tomohiro
author_facet Inoue, Takeshi
Morita, Masahiro
Hijikata, Atsushi
Fukuda-Yuzawa, Yoko
Adachi, Shungo
Isono, Kyoichi
Ikawa, Tomokatsu
Kawamoto, Hiroshi
Koseki, Haruhiko
Natsume, Tohru
Fukao, Taro
Ohara, Osamu
Yamamoto, Tadashi
Kurosaki, Tomohiro
author_sort Inoue, Takeshi
collection PubMed
description The CCR4–NOT deadenylase complex plays crucial roles in mRNA decay and translational repression induced by poly(A) tail shortening. Although the in vitro activities of each component of this complex have been well characterized, its in vivo role in immune cells remains unclear. Here we show that mice lacking the CNOT3 subunit of this complex, specifically in B cells, have a developmental block at the pro- to pre–B cell transition. CNOT3 regulated generation of germline transcripts in the V(H) region of the immunoglobulin heavy chain (Igh) locus, compaction of the locus, and subsequent Igh gene rearrangement and destabilized tumor suppressor p53 mRNA. The developmental defect in the absence of CNOT3 could be partially rescued by ablation of p53 or introduction of a pre-rearranged Igh transgene. Thus, our data suggest that the CCR4–NOT complex regulates B cell differentiation by controlling Igh rearrangement and destabilizing p53 mRNA.
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spelling pubmed-45480562016-02-24 CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability Inoue, Takeshi Morita, Masahiro Hijikata, Atsushi Fukuda-Yuzawa, Yoko Adachi, Shungo Isono, Kyoichi Ikawa, Tomokatsu Kawamoto, Hiroshi Koseki, Haruhiko Natsume, Tohru Fukao, Taro Ohara, Osamu Yamamoto, Tadashi Kurosaki, Tomohiro J Exp Med Article The CCR4–NOT deadenylase complex plays crucial roles in mRNA decay and translational repression induced by poly(A) tail shortening. Although the in vitro activities of each component of this complex have been well characterized, its in vivo role in immune cells remains unclear. Here we show that mice lacking the CNOT3 subunit of this complex, specifically in B cells, have a developmental block at the pro- to pre–B cell transition. CNOT3 regulated generation of germline transcripts in the V(H) region of the immunoglobulin heavy chain (Igh) locus, compaction of the locus, and subsequent Igh gene rearrangement and destabilized tumor suppressor p53 mRNA. The developmental defect in the absence of CNOT3 could be partially rescued by ablation of p53 or introduction of a pre-rearranged Igh transgene. Thus, our data suggest that the CCR4–NOT complex regulates B cell differentiation by controlling Igh rearrangement and destabilizing p53 mRNA. The Rockefeller University Press 2015-08-24 /pmc/articles/PMC4548056/ /pubmed/26238124 http://dx.doi.org/10.1084/jem.20150384 Text en © 2015 Inoue et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Inoue, Takeshi
Morita, Masahiro
Hijikata, Atsushi
Fukuda-Yuzawa, Yoko
Adachi, Shungo
Isono, Kyoichi
Ikawa, Tomokatsu
Kawamoto, Hiroshi
Koseki, Haruhiko
Natsume, Tohru
Fukao, Taro
Ohara, Osamu
Yamamoto, Tadashi
Kurosaki, Tomohiro
CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability
title CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability
title_full CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability
title_fullStr CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability
title_full_unstemmed CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability
title_short CNOT3 contributes to early B cell development by controlling Igh rearrangement and p53 mRNA stability
title_sort cnot3 contributes to early b cell development by controlling igh rearrangement and p53 mrna stability
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548056/
https://www.ncbi.nlm.nih.gov/pubmed/26238124
http://dx.doi.org/10.1084/jem.20150384
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