Mechanisms of c-myc-mediated transcriptional repression of growth arrest genes

Gartel, Andrei L.; Shchors, Ksenya

doi:10.1016/s0014-4827(02)00020-4

Cited by 213 publications

(164 citation statements)

References 33 publications

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“…P27 suppresses cyclinE expression and arrests cells in G 1 (22). c-Myc represses the transcription of key growth control and differentiation genes, including p21, p27, and growtharrest and DNA-damage proteins (23,24). In addition, p27 reportedly acts as a barometer for targeted therapies, because reduced p27 levels and p27 mislocalization have potential prognostic and therapeutic implications (25).…”

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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“…There were two binding sits of SP1 nearby the promoter region of Cdk2 (Shiffman et al, 1996) and p21 (Gartel et al, 2001;Gartel and Shchors, 2003), and one binding sit of E box sequence upstream to the Cdk4 transcriptional-starting site (Hermeking et al, 2000). It is, therefore, possible that Cdk2, Cdk4, and p21 are molecular targets directly regulated by c-myc.…”

Section: Discussionmentioning

confidence: 99%

Cyclin a but not cyclin D1 is essential for c‐myc‐modulated cell‐cycle progression

Yang

et al. 2006

Journal Cellular Physiology

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The proto-oncogene c-myc is a key player in cell-cycle regulation and is deregulated in a broad range of human cancers and cell proliferation disorders. Here we reported that overexpression of c-myc in human embryonic lung fibroblasts (HEL) that have low endogenous c-myc enriched S phase cells with increased expression of cyclin D3, E, A, Cdk2, and Cdk4, and decreased expression of p21 and p27. To the opposite, using RNAi to downregulate c-myc expression in A549 cells that have high endogenous c-myc enriched G1 phase cells with decreased expression of cyclin D3, E, A, Cdk2, Cdk4, and increased expression of p21 and p27. We found that cyclin A expression was the most susceptive to changes in c-myc levels and essential in c-myc-modulated cell cycle pathway via co-transfection, however, cyclin D1 showed no change between treated and control groups in either HEL or A549 cells. Our results indicated that upregulation of c-myc expression promotes cell cycling in HEL cells, whereas downregulation of c-myc expression causes G1 phase arrest in A549 cells, and the c-myc-mediated cell-cycle regulation pathway was dependent on cyclin A and involved cyclin D3, E, Cdk2, Cdk4, p21, and p27, but not cyclin D1.

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“…Human c-myc is a transcription factor that is central to regulation of cell growth, proliferation, differentiation and apoptosis [27][28][29][30][31][32][33]. The aberrant overexpression of the c-myc gene is considered to be associated with the progression of many cancers [34].…”

mentioning

confidence: 99%

Roles of flanking sequences in the binding between unimolecular parallel-stranded G-quadruplexes and ligands

et al. 2013

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G-quadruplexes attract more and more attention in recent years. Numerous small molecules which can induce or stabilize the formation of G-quadruplexes have been investigated on the purpose of anticancer drug development. As a motif existed in physiological condition, flanking sequences are an important part of G-quadruplexes but the study on the impact of flanking sequences on (G-quadruplex)-ligand binding is rarely reported. In this paper, the effects of flanking sequences on binding affinity between a series of unimolecular parallel-stranded G-quadruplex sequences derived from c-myc oncogene promoter (termed as c-myc G-quadruplexes) and their ligands are discussed in detail. The results showed that the flanking sequences on c-myc G-quadruplexes play key roles in (G-quadruplex)-ligand interaction. When a c-myc G-quadruplex is bound to its ligands, the flanking sequences might form a binding cavity above the terminal G-quartet, which could provide a suitable site for ligands to dock in. Moreover, the bases on flanking sequences could interact with ligand through - stacking, and finally form a sandwich-stacking mode (terminal G-quartet, ligand and bases on the flanking sequence). This mode could stabilize the (G-quadruplex)-ligand complex effectively and enhance the binding affinity dramatically. However, flanking sequences are also found to exhibit steric hindrance effect which could impede the (G-quadruplex)-ligand binding. G-quadruplex

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Mechanisms of c-myc-mediated transcriptional repression of growth arrest genes

Cited by 213 publications

References 33 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

Cyclin a but not cyclin D1 is essential for c‐myc‐modulated cell‐cycle progression

Roles of flanking sequences in the binding between unimolecular parallel-stranded G-quadruplexes and ligands

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