title: Interactions between SAP155 and FUSE-binding protein-interacting repressor bridges c-Myc and P27Kip1 expression.
abstract: 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.
authors.affiliation: Department of Molecular Diagnosis (F8), Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. kmatsu@faculty.chiba-u.jp
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Matsushita
authors.forename: Mai
authors.initials: M
authors.lastname: Tamura
authors.forename: Nobuko
authors.initials: N
authors.lastname: Tanaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tomonaga
authors.forename: Hisahiro
authors.initials: H
authors.lastname: Matsubara
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shimada
authors.forename: David
authors.initials: D
authors.lastname: Levens
authors.forename: Liusheng
authors.initials: L
authors.lastname: He
authors.forename: Juhong
authors.initials: J
authors.lastname: Liu
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.forename: Fumio
authors.initials: F
authors.lastname: Nomura
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D019927:Cyclin E / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011714:Pyrans / Q000494:pharmacology; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D000072260:RNA Splicing Factors; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000378:metabolism*; D013141:Spiro Compounds / Q000494:pharmacology; D051758:Transcription Factor TFIIH / Q000378:metabolism
chemical_list: D019927:Cyclin E; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D016271:Proto-Oncogene Proteins c-myc; D011714:Pyrans; D012322:RNA Precursors; D000072260:RNA Splicing Factors; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; D013141:Spiro Compounds; C410595:poly-U binding splicing factor 60KDa; C553684:spliceostatin A; C072022:XPBC-ERCC-3 protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051758:Transcription Factor TFIIH; D004265:DNA Helicases