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Haploinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1

FUSE-binding protein (FBP)-interacting repressor (FIR) is a c-myc transcriptional suppressor. A splice variant of FIR that lacks exon 2 in the transcriptional repressor domain (FIRΔexon2) upregulates c-myc transcription by inactivating wild-type FIR. The ratio of FIRΔexon2/FIR mRNA was increased in...

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Autores principales: Matsushita, Kazuyuki, Kitamura, Kouichi, Rahmutulla, Bahityar, Tanaka, Nobuko, Ishige, Takayuki, Satoh, Mamoru, Hoshino, Tyuji, Miyagi, Satoru, Mori, Takeshi, Itoga, Sakae, Shimada, Hideaki, Tomonaga, Takeshi, Kito, Minoru, Nakajima-Takagi, Yaeko, Kubo, Shuji, Nakaseko, Chiaki, Hatano, Masahiko, Miki, Takashi, Matsuo, Masafumi, Fukuyo, Masaki, Kaneda, Atsushi, Iwama, Atsushi, Nomura, Fumio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467136/
https://www.ncbi.nlm.nih.gov/pubmed/25671302
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author Matsushita, Kazuyuki
Kitamura, Kouichi
Rahmutulla, Bahityar
Tanaka, Nobuko
Ishige, Takayuki
Satoh, Mamoru
Hoshino, Tyuji
Miyagi, Satoru
Mori, Takeshi
Itoga, Sakae
Shimada, Hideaki
Tomonaga, Takeshi
Kito, Minoru
Nakajima-Takagi, Yaeko
Kubo, Shuji
Nakaseko, Chiaki
Hatano, Masahiko
Miki, Takashi
Matsuo, Masafumi
Fukuyo, Masaki
Kaneda, Atsushi
Iwama, Atsushi
Nomura, Fumio
author_facet Matsushita, Kazuyuki
Kitamura, Kouichi
Rahmutulla, Bahityar
Tanaka, Nobuko
Ishige, Takayuki
Satoh, Mamoru
Hoshino, Tyuji
Miyagi, Satoru
Mori, Takeshi
Itoga, Sakae
Shimada, Hideaki
Tomonaga, Takeshi
Kito, Minoru
Nakajima-Takagi, Yaeko
Kubo, Shuji
Nakaseko, Chiaki
Hatano, Masahiko
Miki, Takashi
Matsuo, Masafumi
Fukuyo, Masaki
Kaneda, Atsushi
Iwama, Atsushi
Nomura, Fumio
author_sort Matsushita, Kazuyuki
collection PubMed
description FUSE-binding protein (FBP)-interacting repressor (FIR) is a c-myc transcriptional suppressor. A splice variant of FIR that lacks exon 2 in the transcriptional repressor domain (FIRΔexon2) upregulates c-myc transcription by inactivating wild-type FIR. The ratio of FIRΔexon2/FIR mRNA was increased in human colorectal cancer and hepatocellular carcinoma tissues. Because FIRΔexon2 is considered to be a dominant negative regulator of FIR, FIR heterozygous knockout (FIR(+/−)) C57BL6 mice were generated. FIR complete knockout (FIR(−/−)) was embryonic lethal before E9.5; therefore, it is essential for embryogenesis. This strongly suggests that insufficiency of FIR is crucial for carcinogenesis. FIR(+/−) mice exhibited prominent c-myc mRNA upregulation, particularly in the peripheral blood (PB), without any significant pathogenic phenotype. Furthermore, elevated FIRΔexon2/FIR mRNA expression was detected in human leukemia samples and cell lines. Because the single knockout of TP53 generates thymic lymphoma, FIR(+/−)TP53(−/−) generated T-cell type acute lymphocytic/lymphoblastic leukemia (T-ALL) with increased organ or bone marrow invasion with poor prognosis. RNA-sequencing analysis of sorted thymic lymphoma cells revealed that the Notch signaling pathway was activated significantly in FIR(+/−)TP53(−/−) compared with that in FIR(+/+)TP53(−/−) mice. Notch1 mRNA expression in sorted thymic lymphoma cells was confirmed using qRT-PCR. In addition, flow cytometry revealed that c-myc mRNA was negatively correlated with FIR but positively correlated with Notch1 in sorted T-ALL/thymic lymphoma cells. Moreover, the knockdown of TP53 or c-myc using siRNA decreased Notch1 expression in cancer cells. In addition, an adenovirus vector encoding FIRΔexon2 cDNA increased bleomycin-induced DNA damage. Taken together, these data suggest that the altered expression of FIRΔexon2 increased Notch1 at least partially by activating c-Myc via a TP53-independent pathway. In conclusion, the alternative splicing of FIR, which generates FIRΔexon2, may contribute to both colorectal carcinogenesis and leukemogenesis.
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spelling pubmed-44671362015-06-22 Haploinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1 Matsushita, Kazuyuki Kitamura, Kouichi Rahmutulla, Bahityar Tanaka, Nobuko Ishige, Takayuki Satoh, Mamoru Hoshino, Tyuji Miyagi, Satoru Mori, Takeshi Itoga, Sakae Shimada, Hideaki Tomonaga, Takeshi Kito, Minoru Nakajima-Takagi, Yaeko Kubo, Shuji Nakaseko, Chiaki Hatano, Masahiko Miki, Takashi Matsuo, Masafumi Fukuyo, Masaki Kaneda, Atsushi Iwama, Atsushi Nomura, Fumio Oncotarget Research Paper FUSE-binding protein (FBP)-interacting repressor (FIR) is a c-myc transcriptional suppressor. A splice variant of FIR that lacks exon 2 in the transcriptional repressor domain (FIRΔexon2) upregulates c-myc transcription by inactivating wild-type FIR. The ratio of FIRΔexon2/FIR mRNA was increased in human colorectal cancer and hepatocellular carcinoma tissues. Because FIRΔexon2 is considered to be a dominant negative regulator of FIR, FIR heterozygous knockout (FIR(+/−)) C57BL6 mice were generated. FIR complete knockout (FIR(−/−)) was embryonic lethal before E9.5; therefore, it is essential for embryogenesis. This strongly suggests that insufficiency of FIR is crucial for carcinogenesis. FIR(+/−) mice exhibited prominent c-myc mRNA upregulation, particularly in the peripheral blood (PB), without any significant pathogenic phenotype. Furthermore, elevated FIRΔexon2/FIR mRNA expression was detected in human leukemia samples and cell lines. Because the single knockout of TP53 generates thymic lymphoma, FIR(+/−)TP53(−/−) generated T-cell type acute lymphocytic/lymphoblastic leukemia (T-ALL) with increased organ or bone marrow invasion with poor prognosis. RNA-sequencing analysis of sorted thymic lymphoma cells revealed that the Notch signaling pathway was activated significantly in FIR(+/−)TP53(−/−) compared with that in FIR(+/+)TP53(−/−) mice. Notch1 mRNA expression in sorted thymic lymphoma cells was confirmed using qRT-PCR. In addition, flow cytometry revealed that c-myc mRNA was negatively correlated with FIR but positively correlated with Notch1 in sorted T-ALL/thymic lymphoma cells. Moreover, the knockdown of TP53 or c-myc using siRNA decreased Notch1 expression in cancer cells. In addition, an adenovirus vector encoding FIRΔexon2 cDNA increased bleomycin-induced DNA damage. Taken together, these data suggest that the altered expression of FIRΔexon2 increased Notch1 at least partially by activating c-Myc via a TP53-independent pathway. In conclusion, the alternative splicing of FIR, which generates FIRΔexon2, may contribute to both colorectal carcinogenesis and leukemogenesis. Impact Journals LLC 2014-12-31 /pmc/articles/PMC4467136/ /pubmed/25671302 Text en Copyright: © 2015 Matsushita et al. http://creativecommons.org/licenses/by/2.5/ 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 credited.
spellingShingle Research Paper
Matsushita, Kazuyuki
Kitamura, Kouichi
Rahmutulla, Bahityar
Tanaka, Nobuko
Ishige, Takayuki
Satoh, Mamoru
Hoshino, Tyuji
Miyagi, Satoru
Mori, Takeshi
Itoga, Sakae
Shimada, Hideaki
Tomonaga, Takeshi
Kito, Minoru
Nakajima-Takagi, Yaeko
Kubo, Shuji
Nakaseko, Chiaki
Hatano, Masahiko
Miki, Takashi
Matsuo, Masafumi
Fukuyo, Masaki
Kaneda, Atsushi
Iwama, Atsushi
Nomura, Fumio
Haploinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1
title Haploinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1
title_full Haploinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1
title_fullStr Haploinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1
title_full_unstemmed Haploinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1
title_short Haploinsufficiency of the c-myc transcriptional repressor FIR, as a dominant negative-alternative splicing model, promoted p53-dependent T-cell acute lymphoblastic leukemia progression by activating Notch1
title_sort haploinsufficiency of the c-myc transcriptional repressor fir, as a dominant negative-alternative splicing model, promoted p53-dependent t-cell acute lymphoblastic leukemia progression by activating notch1
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467136/
https://www.ncbi.nlm.nih.gov/pubmed/25671302
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