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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Veröffentlicht in:Oncotarget 2015-03, Vol.6 (7), p.5102-5117
Hauptverfasser: 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
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container_issue 7
container_start_page 5102
container_title Oncotarget
container_volume 6
creator 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
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.
doi_str_mv 10.18632/oncotarget.3244
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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.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.3244</identifier><identifier>PMID: 25671302</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Adult ; Alternative Splicing ; Animals ; Disease Progression ; Female ; Haploinsufficiency ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology ; Proto-Oncogene Proteins c-myc - genetics ; Proto-Oncogene Proteins c-myc - metabolism ; Receptor, Notch1 - genetics ; Receptor, Notch1 - metabolism ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; Research Paper ; RNA Splicing Factors ; RNA-Binding Proteins - genetics ; RNA-Binding Proteins - metabolism ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism</subject><ispartof>Oncotarget, 2015-03, Vol.6 (7), p.5102-5117</ispartof><rights>Copyright: © 2015 Matsushita et al. 2015</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c354t-322f24efac4dc40ffbd410bb8ca87545da57bad3bb8996743c6738f99570db523</citedby><cites>FETCH-LOGICAL-c354t-322f24efac4dc40ffbd410bb8ca87545da57bad3bb8996743c6738f99570db523</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467136/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467136/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25671302$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Matsushita, Kazuyuki</creatorcontrib><creatorcontrib>Kitamura, Kouichi</creatorcontrib><creatorcontrib>Rahmutulla, Bahityar</creatorcontrib><creatorcontrib>Tanaka, Nobuko</creatorcontrib><creatorcontrib>Ishige, Takayuki</creatorcontrib><creatorcontrib>Satoh, Mamoru</creatorcontrib><creatorcontrib>Hoshino, Tyuji</creatorcontrib><creatorcontrib>Miyagi, Satoru</creatorcontrib><creatorcontrib>Mori, Takeshi</creatorcontrib><creatorcontrib>Itoga, Sakae</creatorcontrib><creatorcontrib>Shimada, Hideaki</creatorcontrib><creatorcontrib>Tomonaga, Takeshi</creatorcontrib><creatorcontrib>Kito, Minoru</creatorcontrib><creatorcontrib>Nakajima-Takagi, Yaeko</creatorcontrib><creatorcontrib>Kubo, Shuji</creatorcontrib><creatorcontrib>Nakaseko, Chiaki</creatorcontrib><creatorcontrib>Hatano, Masahiko</creatorcontrib><creatorcontrib>Miki, Takashi</creatorcontrib><creatorcontrib>Matsuo, Masafumi</creatorcontrib><creatorcontrib>Fukuyo, Masaki</creatorcontrib><creatorcontrib>Kaneda, Atsushi</creatorcontrib><creatorcontrib>Iwama, Atsushi</creatorcontrib><creatorcontrib>Nomura, Fumio</creatorcontrib><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><title>Oncotarget</title><addtitle>Oncotarget</addtitle><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.</description><subject>Adult</subject><subject>Alternative Splicing</subject><subject>Animals</subject><subject>Disease Progression</subject><subject>Female</subject><subject>Haploinsufficiency</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics</subject><subject>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism</subject><subject>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology</subject><subject>Proto-Oncogene Proteins c-myc - genetics</subject><subject>Proto-Oncogene Proteins c-myc - metabolism</subject><subject>Receptor, Notch1 - genetics</subject><subject>Receptor, Notch1 - metabolism</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>Research Paper</subject><subject>RNA Splicing Factors</subject><subject>RNA-Binding Proteins - genetics</subject><subject>RNA-Binding Proteins - metabolism</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1u1TAQhSMEolXpnhXyAzRt4p_8bJBQRWmlCiRU1tHEHucaHNuyfSvlIXknfFtaijcz8vh8Z-RTVe_b5rwdOkYvvJM-Q1wwnzPK-avquB35WFMh2OsX_VF1mtLPphzB-4GOb6sjKrq-ZQ09rn5fQ7DeuLTX2kiDTm7Ea5J3SGS9bpLkCC7JaEI23oElEUPElHwkVzffzwgkAkT51ThwmThcIJt7rMFmjO6hJynYQnYLWb1Ce0ZC9KvPqEgQrFYY0Cks2rtaorUE5D4jsdsadn62kLKRxOL-F64GDtLl4F5WIfNW3haDYlLYX32Wu_Zd9UaDTXj6t55UP64-311e17ffvtxcfrqtJRM814xSTTlqkFxJ3mg9K9428zxIGHrBhQLRz6BYuRnHrudMdj0b9DiKvlGzoOyk-vjIDft5RSXL_hHsFKJZIW6TBzP9P3FmNy3-fuL88PFdATSPABl9ShH1s7Ztpod0p3_pTod0i-TDS89nwVOW7A9_PKtM</recordid><startdate>20150310</startdate><enddate>20150310</enddate><creator>Matsushita, Kazuyuki</creator><creator>Kitamura, Kouichi</creator><creator>Rahmutulla, Bahityar</creator><creator>Tanaka, Nobuko</creator><creator>Ishige, Takayuki</creator><creator>Satoh, Mamoru</creator><creator>Hoshino, Tyuji</creator><creator>Miyagi, Satoru</creator><creator>Mori, Takeshi</creator><creator>Itoga, Sakae</creator><creator>Shimada, Hideaki</creator><creator>Tomonaga, Takeshi</creator><creator>Kito, Minoru</creator><creator>Nakajima-Takagi, Yaeko</creator><creator>Kubo, Shuji</creator><creator>Nakaseko, Chiaki</creator><creator>Hatano, Masahiko</creator><creator>Miki, Takashi</creator><creator>Matsuo, Masafumi</creator><creator>Fukuyo, Masaki</creator><creator>Kaneda, Atsushi</creator><creator>Iwama, Atsushi</creator><creator>Nomura, Fumio</creator><general>Impact Journals LLC</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20150310</creationdate><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><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></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c354t-322f24efac4dc40ffbd410bb8ca87545da57bad3bb8996743c6738f99570db523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adult</topic><topic>Alternative Splicing</topic><topic>Animals</topic><topic>Disease Progression</topic><topic>Female</topic><topic>Haploinsufficiency</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics</topic><topic>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism</topic><topic>Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology</topic><topic>Proto-Oncogene Proteins c-myc - genetics</topic><topic>Proto-Oncogene Proteins c-myc - metabolism</topic><topic>Receptor, Notch1 - genetics</topic><topic>Receptor, Notch1 - metabolism</topic><topic>Repressor Proteins - genetics</topic><topic>Repressor Proteins - metabolism</topic><topic>Research Paper</topic><topic>RNA Splicing Factors</topic><topic>RNA-Binding Proteins - genetics</topic><topic>RNA-Binding Proteins - metabolism</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><toplevel>online_resources</toplevel><creatorcontrib>Matsushita, Kazuyuki</creatorcontrib><creatorcontrib>Kitamura, Kouichi</creatorcontrib><creatorcontrib>Rahmutulla, Bahityar</creatorcontrib><creatorcontrib>Tanaka, Nobuko</creatorcontrib><creatorcontrib>Ishige, Takayuki</creatorcontrib><creatorcontrib>Satoh, Mamoru</creatorcontrib><creatorcontrib>Hoshino, Tyuji</creatorcontrib><creatorcontrib>Miyagi, Satoru</creatorcontrib><creatorcontrib>Mori, Takeshi</creatorcontrib><creatorcontrib>Itoga, Sakae</creatorcontrib><creatorcontrib>Shimada, Hideaki</creatorcontrib><creatorcontrib>Tomonaga, Takeshi</creatorcontrib><creatorcontrib>Kito, Minoru</creatorcontrib><creatorcontrib>Nakajima-Takagi, Yaeko</creatorcontrib><creatorcontrib>Kubo, Shuji</creatorcontrib><creatorcontrib>Nakaseko, Chiaki</creatorcontrib><creatorcontrib>Hatano, Masahiko</creatorcontrib><creatorcontrib>Miki, Takashi</creatorcontrib><creatorcontrib>Matsuo, Masafumi</creatorcontrib><creatorcontrib>Fukuyo, Masaki</creatorcontrib><creatorcontrib>Kaneda, Atsushi</creatorcontrib><creatorcontrib>Iwama, Atsushi</creatorcontrib><creatorcontrib>Nomura, Fumio</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Matsushita, Kazuyuki</au><au>Kitamura, Kouichi</au><au>Rahmutulla, Bahityar</au><au>Tanaka, Nobuko</au><au>Ishige, Takayuki</au><au>Satoh, Mamoru</au><au>Hoshino, Tyuji</au><au>Miyagi, Satoru</au><au>Mori, Takeshi</au><au>Itoga, Sakae</au><au>Shimada, Hideaki</au><au>Tomonaga, Takeshi</au><au>Kito, Minoru</au><au>Nakajima-Takagi, Yaeko</au><au>Kubo, Shuji</au><au>Nakaseko, Chiaki</au><au>Hatano, Masahiko</au><au>Miki, Takashi</au><au>Matsuo, Masafumi</au><au>Fukuyo, Masaki</au><au>Kaneda, Atsushi</au><au>Iwama, Atsushi</au><au>Nomura, Fumio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2015-03-10</date><risdate>2015</risdate><volume>6</volume><issue>7</issue><spage>5102</spage><epage>5117</epage><pages>5102-5117</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>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.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>25671302</pmid><doi>10.18632/oncotarget.3244</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1949-2553
ispartof Oncotarget, 2015-03, Vol.6 (7), p.5102-5117
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1949-2553
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4467136
source MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free E- Journals; PubMed Central Open Access
subjects Adult
Alternative Splicing
Animals
Disease Progression
Female
Haploinsufficiency
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Receptor, Notch1 - genetics
Receptor, Notch1 - metabolism
Repressor Proteins - genetics
Repressor Proteins - metabolism
Research Paper
RNA Splicing Factors
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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
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