Dataset Information

Genetic Variant of C-5434T REN Enhancer on Serum Renin Levels and Binding Pattern of Signal Transducers and Activators Transcription 3.

ABSTRACT: The human renin gene has been widely known to be involved in essential hypertension (EH) pathogenesis. Genetic variant C-5434T of REN enhancer contributed to renin gene transcription and serum renin regulation. However, the mechanism associated with the transcription level changes remains unknown, and only a few reports exist that discussed serum renin levels on C-5434T of REN. Thus, this study aims to investigate the relationship between genetic variant C-5434T of REN enhancer and serum renin levels in Indonesian hypertensive patients. SNP of C-5434T was genotyped in 56 hypertensive patients by using RFLP. The data showed that serum renin is slightly higher in hypertensive patients with the TT genotype (39 ± 10.3) than patients with the CC genotype (33 ± 10.6) but the difference was not statistically significant (p = 0.35). Here, we also present a docking approach for predicting interaction between genetic variant -5434C/T and STAT3 (Signal Transducers and Activators Transcription 3), the predicted transcription factor that regulates renin gene enhancer. The results showed that STAT3-DNA allele T more favorably binds to DNA than STAT3-DNA allele C. These data suggest that the presence of genetic variant C-5434T has changed the binding pattern of STAT3 to REN enhancer. This is likely to influence STAT3 activity to stimulate the expression of renin gene in producing renin.

SUBMITTER: Maslahah I

PROVIDER: S-EPMC4454770 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Genetic Variant of C-5434T REN Enhancer on Serum Renin Levels and Binding Pattern of Signal Transducers and Activators Transcription 3.

Maslahah Imama I Rohman Mohammad Saifur MS Widodo Nashi N Endharti Agustina Tri AT Utomo Didik D

International journal of hypertension 20150521

The human renin gene has been widely known to be involved in essential hypertension (EH) pathogenesis. Genetic variant C-5434T of REN enhancer contributed to renin gene transcription and serum renin regulation. However, the mechanism associated with the transcription level changes remains unknown, and only a few reports exist that discussed serum renin levels on C-5434T of REN. Thus, this study aims to investigate the relationship between genetic variant C-5434T of REN enhancer and serum renin l ...[more]

PMID: 26090220

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Project description:Signal Transducer and Activator of Transcription STAT5 is a key mediator of cell proliferation, differentiation and survival. While STAT5 activity is tightly regulated in normal cells, its constitutive activation directly contributes to oncogenesis and is associated with a broad range of hematological and solid tumor cancers. Therefore the development of compounds able to modulate pathogenic activation of this protein is a very challenging endeavor. A crucial step of drug design is the understanding of the protein conformational features and the definition of putative binding site(s) for such modulators. Currently, there is no structural data available for human STAT5 and our study is the first footprint towards the description of structure and dynamics of this protein. We investigated structural and dynamical features of the two STAT5 isoforms, STAT5a and STAT5b, taken into account their phosphorylation status. The study was based on the exploration of molecular dynamics simulations by different analytical methods. Despite the overall folding similarity of STAT5 proteins, the MD conformations display specific structural and dynamical features for each protein, indicating first, sequence-encoded structural properties and second, phosphorylation-induced effects which contribute to local and long-distance structural rearrangements interpreted as allosteric event. Further examination of the dynamical coupling between distant sites provides evidence for alternative profiles of the communication pathways inside and between the STAT5 domains. These results add a new insight to the understanding of the crucial role of intrinsic molecular dynamics in mediating intramolecular signaling in STAT5. Two pockets, localized in close proximity to the phosphotyrosine-binding site and adjacent to the channel for communication pathways across STAT5, may constitute valid targets to develop inhibitors able to modulate the function-related communication properties of this signaling protein.

Project description:BackgroundSignal transducers and activators of transcription (STAT) transcription factors, a family of genes encoding transcription factors, have been linked to the development of numerous types of tumors. However, there is a relative paucity of a comprehensive investigation of the expression and functional analysis of STATs in ovarian cancer (OV).MethodGene expression profile interaction analysis (GEPI2A), Metascape, The Cancer Genome Atlas (TCGA), Kaplan-Meier Plotter, Linkedomics, and CancerSEA databases were used for expression analysis and functional enrichment of STATs in ovarian cancer patients. We screened potential predictive genes and evaluated their prognostic value by constructing the minor absolute shrinkage and selection operator (LASSO) Cox proportional risk regression model. We explored STAT5A expression and its effects on cell invasion using ovarian cancer cells and a tissue microarray.ResultsThe expression level of STAT1 was higher, but that of STAT2-6 was lower in cancerous ovarian tissues compared to normal tissues, which were closely associated with the clinicopathological features. Low STAT1, high STAT4, and 6 mRNA levels indicated high overall survival. STAT1, 3, 4, and 5A were collectively constructed as prognostic risk models. STAT3, and 5A, up-regulating in the high-risk group, were regarded as risk genes. In subsequent validation, OV patients with a low level of P-STAT5A but not low STAT5A had a longer survival time (P=0.0042). Besides, a negative correlation was found between the expression of STAT5A and invasion of ovarian cancer cells (R= -0.38, p < 0.01), as well as DNA repair function (R= -0.36, p < 0.01). Furthermore, transient overexpression of STAT5A inhibited wound healing (21.8%, P<0.0001) and cell migration to the lower chamber of the Transwell system (29.3%, P<0.0001), which may be achieved by regulating the expression of MMP2.ConclusionIt is suggested that STAT1, STAT4, and STAT6 may be potential targets for the proper treatment of ovarian cancer. STAT5A and P-STAT5A, biomarkers identified in ovarian cancer, may offer new perspectives for predicting prognosis and assessing therapeutic effects.

Dataset Information

Genetic Variant of C-5434T REN Enhancer on Serum Renin Levels and Binding Pattern of Signal Transducers and Activators Transcription 3.

Publications

Genetic Variant of C-5434T REN Enhancer on Serum Renin Levels and Binding Pattern of Signal Transducers and Activators Transcription 3.

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