Splicing factor SF3b as a target of the antitumor natural product pladienolide

Kotake, Yoshihiko; Sagane, Koji; Owa, Takashi; Mimori-Kiyosue, Yuko; Shimizu, Hajime; Uesugi, Mai; Ishihama, Yasushi; Iwata, Masao; Mizui, Yoshiharu

doi:10.1038/nchembio.2007.16

Cited by 569 publications

(656 citation statements)

References 21 publications

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“…A sendai virus vector encoding FIR showed synergistic effects with cisplatin on malignant mesothelioma (28). Furthermore, SF3b is a cancer treatment target (14,29). Since the FIR/FIRDexon2/SAP155 complex is induced in colorectal cancers and disrupts proper FIR premRNA splicing, FIR splicing variants may be novel cancer screening markers (30,31).…”

Section: Discussionmentioning

confidence: 99%

Interactions between SAP155 and FUSE-Binding Protein-Interacting Repressor Bridges c-Myc and P27Kip1 Expression

Matsushita

Tamura

Tanaka

et al. 2013

Molecular Cancer Research

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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 (FIRDexon2). FIR and FIRDexon2 form a homo-or hetero-dimer that complexes with SAP155. Our study indicates that the FIR/FIRDexon2/SAP155 interaction bridges c-Myc and P27 expression. Knockdown of FIR/FIRDexon2 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/FIRDexon2 complex is potentially essential for sustained expression of both P89 and P27. Together, the interaction between SAP155 and FIR/ FIRDexon2 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. Mol Cancer Res; 11(7); 689-98. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Interactions between SAP155 and FUSE-Binding Protein-Interacting Repressor Bridges c-Myc and P27Kip1 Expression

Matsushita

Tamura

Tanaka

et al. 2013

Molecular Cancer Research

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“…9,12 Therefore targeting the spliceosome may be a novel therapeutic approach for the treatment of CLL. Several compounds are available for this purpose, [13][14][15][16] including meayamycin B 17,18 and the structurally related spliceostatin A (SSA). 16 SSA is a synthetically modified analog of the natural product FR901464, 19 while meayamycin B is prepared by total synthesis.…”

Section: Introductionmentioning

confidence: 99%

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

et al. 2015

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The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA), is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose-and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression.However, normal B and T cells were less sensitive than CLL cells (p=0.006 and p<0.001, respectively).

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“…32,34,83 A mapping of these mutations on the pseudo-atomic model showed that they cluster around 2 regions in the SF3b structure (Fig. S25 and Video S7).…”

Section: Sf3b145 -A Stem Loop Binding Protein Containing An Rnase H-lmentioning

confidence: 99%

“…S27), analogous to its role in the U11/U12 di-snRNP. SSA is also known to bind to SF3b130 and SF3b155 34 and based on our SF3b pseudo-atomic model (Fig. 2B), we conjecture that these interactions might lock the SF3b130-SF3b155 interaction (Fig.…”

Section: Sf3b -A Fuzzy Complexmentioning

confidence: 99%

“…Further understanding of the detailed structural features of this complex and mechanistic features is desirable as it is a target for many antitumor drugs. [32][33][34][35] It is more than a decade since the cryo-EM map of the human SF3b complex was obtained and the lack of structural information has left a substantial part of the density unexplained. With the remarkable expansion of the list of known 3D structures of proteins, we now have better opportunities to recognize structures of these components.…”

Section: Introductionmentioning

confidence: 99%

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Structural and mechanistic insights into human splicing factor SF3b complex derived using an integrated approach guided by the cryo-EM density maps

et al. 2016

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Pre-mRNA splicing in eukaryotes is performed by the spliceosome, a highly complex macromolecular machine. SF3b is a multi-protein complex which recognizes the branch point adenosine of pre-mRNA as part of a larger U2 snRNP or U11/U12 di-snRNP in the dynamic spliceosome machinery. Although a cryo-EM map is available for human SF3b complex, the structure and relative spatial arrangement of all components in the complex are not yet known. We have recognized folds of domains in various proteins in the assembly and generated comparative models. Using an integrative approach involving structural and other experimental data, guided by the available cryo-EM density map, we deciphered a pseudoatomic model of the closed form of SF3b which is found to be a "fuzzy complex" with highly flexible components and multiplicity of folds. Further, the model provides structural information for 5 proteins (SF3b10, SF3b155, SF3b145, SF3b130 and SF3b14b) and localization information for 4 proteins (SF3b10, SF3b145, SF3b130 and SF3b14b) in the assembly for the first time. Integration of this model with the available U11/U12 di-snRNP cryo-EM map enabled elucidation of an open form. This now provides new insights on the mechanistic features involved in the transition between closed and open forms pivoted by a hinge region in the SF3b155 protein that also harbors cancer causing mutations. Moreover, the open form guided model of the 5 0 end of U12 snRNA, which includes the branch point duplex, shows that the architecture of SF3b acts as a scaffold for U12 snRNA: pre-mRNA branch point duplex formation with potential implications for branch point adenosine recognition fidelity.

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Splicing factor SF3b as a target of the antitumor natural product pladienolide

Cited by 569 publications

References 21 publications

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

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

Structural and mechanistic insights into human splicing factor SF3b complex derived using an integrated approach guided by the cryo-EM density maps

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