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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.
AuthorsKazuyuki Matsushita, Mai Tamura, Nobuko Tanaka, Takeshi Tomonaga, Hisahiro Matsubara, Hideaki Shimada, David Levens, Liusheng He, Juhong Liu, Minoru Yoshida, Fumio Nomura
JournalMolecular cancer research : MCR (Mol Cancer Res) Vol. 11 Issue 7 Pg. 689-98 (Jul 2013) ISSN: 1557-3125 [Electronic] United States
PMID23594796 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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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