| First Author | Rahmutulla B | Year | 2014 |
| Journal | Oncotarget | Volume | 5 |
| Issue | 9 | Pages | 2404-17 |
| PubMed ID | 24811221 | Mgi Jnum | J:346841 |
| Mgi Id | MGI:6512278 | Doi | 10.18632/oncotarget.1650 |
| Citation | Rahmutulla B, et al. (2014) Alternative splicing of FBP-interacting repressor coordinates c-Myc, P27Kip1/cyclinE and Ku86/XRCC5 expression as a molecular sensor for bleomycin-induced DNA damage pathway. Oncotarget 5(9):2404-17 |
| abstractText | The far-upstream element-binding protein-interacting repressor (FIR) is a c-myc transcriptional suppressor. FIR is alternatively spliced to lack the transcriptional repression domain within exon 2 (FIRDeltaexon2) in colorectal cancers. FIR and FIRDeltaexon2 form homo- or heterodimers that complex with SAP155. SAP155, a subunit of the essential splicing factor 3b subcomplex in the spliceosome, is required for proper P27Kip1 pre-mRNA splicing, and P27Kip1 arrests cells at G1. In contrast, FIR was co-immunoprecipitated with Ku86 and DNA-PKcs. siRNA against Ku86/Ku70 decreased FIR and P27Kip1 expression, whereas siRNA against FIR decreased Ku86/XRCC5 and P27Kip1 expression. Thus the mechanical interaction of FIR/FIRDeltaexon2/SAP155 bridges c-myc and P27Kip1 expression, potentially integrates cell-cycle progression and c-myc transcription in cell. Bleomycin(BLM) is an anticancer agent that introduces DNA breaks. Because DNA breaks generate the recruitment of Ku86/Ku70 to bind to the broken DNA ends, the possible involvement of FIR and Ku86/Ku70 interaction in the BLM-induced DNA damage repair response was investigated in this study. First, BLM treatment reduced SAP155 expression and increased FIR and FIRDeltaexon2 mRNA expression as well as the ratio of FIRDeltaexon2:FIR in hepatoblastoma cells (HLE and HLF). Second, FIR or FIRDeltaexon2 adenovirus vectors (Ad-FIR or Ad-FIRDeltaexon2) increased Ku86/Ku70 and P27Kip1 expression in vitro. Third, BLM decreased P27Kip1 protein expression, whereas increased P27Kip1 and gammaH2AX expression with Ad-FIRDeltaexon2. Together, the interaction of FIR/SAP155 modulates FIR splicing and involves in cell-cycle control or cell fate via P27Kip1 and c-myc in BLM-induced DNA damage pathway. This novel function of FIR splicing will contribute to clinical studies of cancer management through elucidating the mechanical interaction of FIR/FIRDeltaexon2/SAP155 as a potential target for cancer treatment. |
