The –928 G/C and –362 G/C Single-Nucleotide Polymorphisms in the Promoter of MCP-1: Increased Transcriptional Activity and Novel Binding Sites

2010 ◽  
Vol 29 (3) ◽  
pp. 242-247 ◽  
Author(s):  
Paul Nyquist ◽  
Jianhua Zhang ◽  
Thomas J. De Graba
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Binding Sites ◽  
Transcriptional Activity ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

scholarly journals Identification of Upstream Stimulatory Factor Binding Sites in the Human IGFBP3 Promoter and Potential Implication of Adjacent Single-Nucleotide Polymorphisms and Responsiveness to Insulin

Endocrinology ◽  
2007 ◽  
Vol 148 (12) ◽  
pp. 6007-6018 ◽  
Author(s):  
Jean Paquette ◽  
Benoit Bessette ◽  
Elisabeth Ledru ◽  
Cheri Deal
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Binding Site ◽  
Transcriptional Activity ◽  
Luciferase Activity ◽  
Nucleotide Polymorphisms ◽  
Upstream Stimulatory Factor ◽  
Single Nucleotide ◽  
Potential Implication ◽  
Stimulatory Factor ◽  
Igfbp 3

The actions of IGFs are regulated at various levels. One mechanism involves binding to IGF-binding protein-3 (IGFBP-3) for transport, thus governing bioavailability. IGFBP3 transcription is modulated by many hormones and agents that stimulate or inhibit growth. We have previously shown in pediatric and adult cohorts a correlation between IGFBP-3 serum levels and two single-nucleotide polymorphisms (SNPs) located within the minimal promoter (−202 A/C and −185 C/T). Functionality of these SNPs was further explored in hepatic adenocarcinoma-derived SK-HEP-1 cells using transient transfections of luciferase constructs driven by different haplotypes of the IGFBP3 promoter. Basal luciferase activity revealed a significant haplotype-dependent transcriptional activity (at nucleotides −202 and −185, AC > CC, P < 0.001; AC > CT, P < 0.001; AC > AT, P < 0.001). Insulin treatment produced a similar haplotype dependence of luciferase activity (AC > CC, P = 0.002; AC > CT, P < 0.001; AC > AT, P = 0.011). However, induction ratios (insulin/control) for CC and AT were significantly higher compared with AC and CT (CC > AC, P = 0.03; CC > CT, P = 0.03; AT > AC, P = 0.03; AT > CT, P = 0.04). Gel retardation assays were used to identify upstream stimulatory factor (USF-1 and USF-2) methylation-dependent binding to E-box motifs located between the SNPs. Mutation of the USF binding site resulted in a significant loss of insulin stimulation of luciferase activity in the transfection assay. Chromatin immunoprecipitation with anti-USF-1/-2 showed an enrichment of IGFBP3 promoter in insulin-treated cells compared with unstimulated cells. Bisulfite sequencing of genomic DNA revealed that CpG methylation in the region of USF binding was haplotype dependent. In summary, we report a methylation-dependent USF binding site influencing the basal and insulin-stimulated transcriptional activity of the IGFBP3 promoter.

scholarly journals Single Nucleotide Polymorphisms in MiRNA Binding Sites of Nucleotide Excision Repair-Related Genes Predict Clinical Benefit of Oxaliplatin in FOLFOXIRI Plus Bevacizumab: Analysis of the TRIBE Trial

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1742
Author(s):  
Mitsukuni Suenaga ◽  
Marta Schirripa ◽  
Shu Cao ◽  
Wu Zhang ◽  
Dongyun Yang ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Nucleotide Excision Repair ◽  
Binding Sites ◽  
Excision Repair ◽  
Dependent Manner ◽  
Nucleotide Polymorphisms ◽  
Wild Type ◽  
First Line ◽  
Single Nucleotide ◽  
Nucleotide Excision

Background: The nucleotide excision repair (NER) pathway participates in platinum-induced DNA damage repair. Single nucleotide polymorphisms (SNPs) in miRNA-binding sites in the NER genes RPA2 and GTF2H1 are associated with the risk of colorectal cancer (CRC). Here, we analyzed whether RPA2 and GTF2H1 SNPs predict the efficacy of oxaliplatin in metastatic CRC (mCRC) patients. Patients and methods: Genomic DNA was extracted from blood samples from 457 patients with mCRC enrolled in the TRIBE trial, which compared first-line FOLFOXIRI plus bevacizumab (BEV) (n = 230, discovery cohort) and first-line FOLFIRI plus BEV (n = 227, control cohort). SNPs were analyzed by PCR-based direct sequencing. Results: In the FOLFOXIRI + BEV-treated cohort expressing wild-type KRAS, progression-free survival (PFS) was shorter for the RPA2 rs7356 C/C variant subgroup than the any T allele subgroup in univariate analysis (9.1 versus 13.3 months respectively, hazard ratio (HR) 2.32, 95% confidence interval (CI): 1.07–5.03, p = 0.020) and this remained significant in multivariable analysis (HR 2.97, 95%CI: 1.27–6.94, p = 0.012). A similar trend was observed for overall survival. In contrast, patients expressing mutant RAS and RPA2 rs7356 C/C variant had longer PFS with FOLFOXIRI + BEV than with FOLFIRI + BEV (12.1 versus 7.6 months, HR 0.23, 95%CI: 0.09–0.62, p = 0.002) but no superiority of FOLFOXIRI + BEV was observed for the RAS mutant, RPA2 rs7356 any T variant subgroup (11.7 versus 9.6 months, HR 0.77, 95%CI: 0.56–1.07, p = 0.12) or the RAS wild-type, RPA2 rs7356 C/C variant subgroup. Conclusion: RPA2 SNPs may serve as predictive and prognostic markers of oxaliplatin responsiveness in a RAS status-dependent manner in mCRC patients receiving FOLFOXIRI + BEV.

Sign in / Sign up

Export Citation Format

Share Document