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.
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.
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FBP相互作用的阻遏物坐标C-MYC，P27KIP1/Cycline和KU86/XRCC5表达的替代剪接作为博来霉素诱导的DNA损伤途径的分子传感器。
DOI：
10.18632/oncotarget.1650
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发表时间：
2014-05-15
期刊：
影响因子：
--
通讯作者：
Nomura F
中科院分区：
文献类型：
--
作者：
Rahmutulla B;Matsushita K;Satoh M;Seimiya M;Tsuchida S;Kubo S;Shimada H;Ohtsuka M;Miyazaki M;Nomura F
远上游元件结合蛋白相互作用抑制子（FIR）是c-myc转录抑制子。在结直肠癌中，FIR被选择性剪接以缺失外显子2内的转录抑制结构域（FIRΔ exon 2）。FIR和FIRΔ外显子2形成与SAP 155复合的同源或异源二聚体。SAP 155是剪接体中必需剪接因子3b亚复合物的一个亚单位，是P27 Kip 1前体mRNA正确剪接所必需的，P27 Kip 1将细胞阻滞在G1期。相反，FIR与Ku 86和DNA-PKcs共免疫沉淀。针对Ku 86/Ku 70的siRNA降低FIR和P27 Kip 1的表达，而针对FIR的siRNA降低Ku 86/XRCC 5和P27 Kip 1的表达。因此，FIR/FIRΔ exon 2/SAP 155的机械相互作用可能是c-myc和P27 Kip 1表达的桥梁，整合了细胞周期进程和c-myc转录。博来霉素（BLM）是一种引入DNA断裂的抗癌剂。由于DNA断裂产生Ku 86/Ku 70的募集结合到断裂的DNA末端，FIR和Ku 86/Ku 70相互作用的可能参与在BLM诱导的DNA损伤修复反应在这项研究中进行了调查。首先，BLM处理降低肝母细胞瘤细胞（HLE和HLF）中SAP 155的表达，增加FIR和FIRΔ exon 2 mRNA的表达以及FIRΔ exon 2：FIR的比率。第二，FIR或FIRΔ exon 2腺病毒载体（Ad-FIR或Ad-FIRΔ exon 2）在体外增加Ku 86/Ku 70和P27 Kip 1的表达。第三，BLM降低P27 Kip 1蛋白表达，而增加Ad-FIRΔ exon 2的P27 Kip 1和γ H2 AX表达。在BLM诱导的DNA损伤途径中，FIR/SAP 155相互作用调节FIR剪接，并通过P27 Kip 1和c-myc参与细胞周期调控或细胞命运。FIR剪接的这种新功能将有助于阐明FIR/FIRΔ exon 2/SAP 155作为癌症治疗的潜在靶点的机械相互作用，从而有助于癌症管理的临床研究。
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 (FIRΔexon2) in colorectal cancers. FIR and FIRΔexon2 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/FIRΔexon2/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 FIRΔexon2 mRNA expression as well as the ratio of FIRΔexon2:FIR in hepatoblastoma cells (HLE and HLF). Second, FIR or FIRΔexon2 adenovirus vectors (Ad-FIR or Ad-FIRΔexon2) increased Ku86/Ku70 and P27Kip1 expression in vitro. Third, BLM decreased P27Kip1 protein expression, whereas increased P27Kip1 and γH2AX expression with Ad-FIRΔexon2. 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/FIRΔexon2/SAP155 as a potential target for cancer treatment.
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影响因子：
16.8
作者：
Kouzine, Fedor;Gupta, Ashutosh;Baranello, Laura;Wojtowicz, Damian;Ben-Aissa, Khadija;Liu, Juhong;Przytycka, Teresa M.;Levens, David
通讯作者：
Levens, David
影响因子：
11.2
作者：
Matsushita, K;Tomonaga, T;Ochiai, T
通讯作者：
Ochiai, T
影响因子：
4.8
作者：
Kimura, K;Nozaki, N;Kikuchi, A
通讯作者：
Kikuchi, A
影响因子：
64.5
作者：
Kouzine F;Wojtowicz D;Yamane A;Resch W;Kieffer-Kwon KR;Bandle R;Nelson S;Nakahashi H;Awasthi P;Feigenbaum L;Menoni H;Hoeijmakers J;Vermeulen W;Ge H;Przytycka TM;Levens D;Casellas R
通讯作者：
Casellas R
DOI：
10.1073/pnas.041603298
发表时间：
2001-02-27
影响因子：
11.1
作者：
Abdel-Rahman, WM;Katsura, K;Edwards, PAW
通讯作者：
Edwards, PAW