| First Author | Matsushita K | Year | 2015 |
| Journal | Oncotarget | Volume | 6 |
| Issue | 7 | Pages | 5102-17 |
| PubMed ID | 25671302 | Mgi Jnum | J:233347 |
| Mgi Id | MGI:5781283 | Doi | 10.18632/oncotarget.3244 |
| Citation | Matsushita K, et al. (2015) 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. Oncotarget 6(7):5102-17 |
| abstractText | 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 (FIRDeltaexon2) upregulates c-myc transcription by inactivating wild-type FIR. The ratio of FIRDeltaexon2/FIR mRNA was increased in human colorectal cancer and hepatocellular carcinoma tissues. Because FIRDeltaexon2 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 FIRDeltaexon2/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 FIRDeltaexon2 cDNA increased bleomycin-induced DNA damage. Taken together, these data suggest that the altered expression of FIRDeltaexon2 increased Notch1 at least partially by activating c-Myc via a TP53-independent pathway. In conclusion, the alternative splicing of FIR, which generates FIRDeltaexon2, may contribute to both colorectal carcinogenesis and leukemogenesis. |
