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.
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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DOI：
10.18632/oncotarget.3244
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发表时间：
2015-03-10
期刊：
影响因子：
--
通讯作者：
Nomura F
中科院分区：
文献类型：
--
作者：
Matsushita K;Kitamura K;Rahmutulla B;Tanaka N;Ishige T;Satoh M;Hoshino T;Miyagi S;Mori T;Itoga S;Shimada H;Tomonaga T;Kito M;Nakajima-Takagi Y;Kubo S;Nakaseko C;Hatano M;Miki T;Matsuo M;Fukuyo M;Kaneda A;Iwama A;Nomura F
FUSE结合蛋白（FBP）相互作用阻遏物（FIR）是一种c-myc转录抑制因子。在转录抑制子结构域中缺少外显子2的FIR剪接变体（FIRΔ exon 2）通过使野生型FIR失活而上调c-myc转录。大肠癌和肝细胞癌组织中FIRΔ exon 2/FIR mRNA比值升高。因为FIRΔ外显子2被认为是FIR的显性负调控因子，所以产生FIR杂合敲除（FIR+/-）C57 BL 6小鼠。FIR完全敲除（FIR-/-）在E9.5之前是胚胎致死的;因此，它对胚胎发生是必需的。这有力地表明，FIR不足是至关重要的致癌作用。FIR+/-小鼠表现出显著的c-myc mRNA上调，特别是在外周血（PB）中，没有任何显著的致病表型。此外，在人白血病样品和细胞系中检测到FIRΔ exon 2/FIR mRNA表达升高。由于TP 53的单一敲除产生胸腺淋巴瘤，FIR+/-TP 53-/-产生T细胞型急性淋巴细胞/淋巴母细胞白血病（T-ALL），器官或骨髓浸润增加，预后不良。分选的胸腺淋巴瘤细胞的RNA测序分析显示，与FIR+/+ TP 53 −/−小鼠相比，FIR +/− TP 53 −/−小鼠的Notch信号通路被显著激活。使用qRT-PCR确认分选的胸腺淋巴瘤细胞中的Notch 1 mRNA表达。流式细胞仪检测显示，在分选的T-ALL/胸腺淋巴瘤细胞中，c-myc mRNA与FIR呈负相关，而与Notch 1呈正相关。此外，使用siRNA敲低TP 53或c-myc降低了癌细胞中Notch 1的表达。此外，编码FIRΔ exon 2 cDNA的腺病毒载体增加博莱霉素诱导的DNA损伤。综上所述，这些数据表明FIRΔ外显子2的表达改变至少部分地通过TP 53非依赖性途径激活c-Myc来增加Notch 1。总之，FIR的选择性剪接，产生FIRΔ外显子2，可能有助于结直肠癌和白血病的发生。
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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