Interactions between SAP155 and FUSE-binding protein-interacting repressor bridges c-Myc and P27Kip1 expression.
Interactions between SAP155 and FUSE-binding protein-interacting repressor bridges c-Myc and P27Kip1 expression.
复制标题
SAP155与融合结合蛋白相互作用的阻遏桥C-MYC和P27KIP1表达之间的相互作用。
DOI：
10.1158/1541-7786.mcr-12-0673
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发表时间：
2013-07
期刊：
影响因子：
--
通讯作者：
Nomura F
中科院分区：
文献类型：
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作者：
Matsushita K;Tamura M;Tanaka N;Tomonaga T;Matsubara H;Shimada H;Levens D;He L;Liu J;Yoshida M;Nomura F
癌基因c-Myc在细胞增殖、凋亡和肿瘤发生中起关键作用，但驱动这种活性的确切机制仍然很大程度上不清楚。P27Kip1(CDKN1B)阻止细胞在G1期，而SAP155(SF3B1)是剪接体的基本剪接因子3b(SF3B)亚单位，是正确的P27前mRNA剪接所必需的。融合结合蛋白相互作用抑制子(FIR)是缺失外显子5的PUF60的剪接变异体，是c-Myc转录靶点，可抑制Δ解旋酶p89(ERCC3)，在缺乏外显子2转录抑制域(FIR)的结直肠癌中可选择性剪接。FIR和FIRΔ外显子2形成与SAP155络合的同源或异源二聚体。我们的研究表明，FIR/FIRΔ外显子2/SAP155相互作用连接了c-Myc和P27的表达。敲除FIR/FIRΔ外显子2或SAP155可降低p27的表达，抑制其前剪接，降低CDK2/Cyclin E的表达。此外，天然的SF3B抑制剂Spliceostatin A通过破坏P27的前mRNA剪接显著抑制P27的表达，并降低CDK2/Cyclin E的表达。在切除的人类结直肠癌组织中，另一个FIR靶点p89的表达增加。然而，对P27和P89表达的影响并不是简单或直接与FIR表达水平的改变有关，这表明SAP155/FIR/FIRΔ外显子2的机械或物理相互作用对于P89和P27的持续表达可能是必不可少的。总之，SAP155和FIR/FIRΔ外显子2之间的相互作用不仅通过改变P27和P89的表达来整合细胞周期进展和c-Myc转录，而且表明这种相互作用是癌症筛查和治疗的潜在靶点。
Oncogenic c-Myc plays a critical role in cell proliferation, apoptosis, and tumorigenesis, but the precise mechanisms that drive this activity remain largely unknown. P27Kip1 (CDKN1B) arrests cells in G1, and SAP155 (SF3B1), a subunit of the essential splicing factor 3b (SF3b) subcomplex of the spliceosome, is required for proper P27 pre-mRNA splicing. FUSE-binding protein-interacting repressor (FIR), a splicing variant of PUF60 lacking exon5, is a c-Myc transcriptional target that suppresses the DNA helicase p89 (ERCC3) and is alternatively spliced in colorectal cancer lacking the transcriptional repression domain within exon 2 (FIRΔexon2). FIR and FIRΔexon2 form a homo- or hetero-dimer that complexes with SAP155. Our study indicates that the FIR/FIRΔexon2/SAP155 interaction bridges c-Myc and P27 expression. Knockdown of FIR/FIRΔexon2 or SAP155 reduced p27 expression, inhibited its pre-mRNA splicing, and reduced CDK2/Cyclin E expression. Moreover, spliceostatin A, a natural SF3b inhibitor, markedly inhibited P27 expression by disrupting its pre-mRNA splicing and reduced CDK2/Cyclin E expression. The expression of P89, another FIR target, was increased in excised human colorectal cancer tissues. Knockdown of FIR reduced P89; however, the effects on P27 and P89 expression are not simply or directly related to altered FIR expression levels, indicating that the mechanical or physical interaction of the SAP155/FIR/FIRΔexon2 complex is potentially essential for sustained expression of both P89 and P27. Together, the interaction between SAP155 and FIR/FIRΔexon2 not only integrates cell-cycle progression and c-Myc transcription by modifying P27 and P89 expression but also suggests that the interaction is a potential target for cancer screening and treatment.