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.
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Authors | Kazuyuki Matsushita, Mai Tamura, Nobuko Tanaka, Takeshi Tomonaga, Hisahiro Matsubara, Hideaki Shimada, David Levens, Liusheng He, Juhong Liu, Minoru Yoshida, Fumio Nomura |
Journal | Molecular cancer research : MCR
(Mol Cancer Res)
Vol. 11
Issue 7
Pg. 689-98
(Jul 2013)
ISSN: 1557-3125 [Electronic] United States |
PMID | 23594796
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | ©2013 AACR |
Chemical References |
- Cyclin E
- DNA-Binding Proteins
- Phosphoproteins
- Proto-Oncogene Proteins c-myc
- Pyrans
- RNA Precursors
- RNA Splicing Factors
- RNA, Small Interfering
- RNA-Binding Proteins
- Repressor Proteins
- Ribonucleoprotein, U2 Small Nuclear
- SF3B1 protein, human
- Spiro Compounds
- poly-U binding splicing factor 60KDa
- spliceostatin A
- XPBC-ERCC-3 protein
- Cyclin-Dependent Kinase Inhibitor p27
- Transcription Factor TFIIH
- DNA Helicases
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Topics |
- Alternative Splicing
(genetics)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Colonic Neoplasms
(metabolism, pathology)
- Cyclin E
(metabolism)
- Cyclin-Dependent Kinase Inhibitor p27
(genetics, metabolism)
- DNA Helicases
(metabolism)
- DNA-Binding Proteins
(metabolism)
- G1 Phase Cell Cycle Checkpoints
(drug effects)
- Gene Knockdown Techniques
- Humans
- Models, Biological
- Phosphoproteins
(metabolism)
- Protein Binding
(drug effects)
- Proto-Oncogene Proteins c-myc
(metabolism)
- Pyrans
(pharmacology)
- RNA Precursors
(genetics, metabolism)
- RNA Splicing Factors
- RNA, Small Interfering
(metabolism)
- RNA-Binding Proteins
(genetics, metabolism)
- Repressor Proteins
(genetics, metabolism)
- Ribonucleoprotein, U2 Small Nuclear
(metabolism)
- Spiro Compounds
(pharmacology)
- Transcription Factor TFIIH
(metabolism)
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