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Epigenetic regulation by G protein alpha12 in human cancer cells and vascular endothelial cells

Other Titles
 G단백질 알파 12에 의한 암세포와 혈관내피세포의 epigenetic 조절 
Authors
 이현정 
Issue Date
2015
Description
의과대학/박사
Abstract
Heterotrimeric guanine nucleotide binding proteins (G proteins) transmit a variety of extracellular signals from cell surface G protein-coupled receptors (GPCRs) to intracellular effector molecules.

Gα12/13-mediated signals formed networks with other signaling proteins at various levels, from cell surface receptors to transcription factors, to regulate cellular responses. The G12 subfamily is composed of Gα12 and Gα13. Accumulating evidence indicates that Gα12/13-mediated signaling pathways are involved in a variety of physiological processes, including embryonic development, cell growth, cell polarity and migration, angiogenesis, platelet activation, immune response, apoptosis, and neuronal responses.

Epigenetic mechanisms denote gene expression variability without coding sequence alteration. Epigenetic machinery includes DNA methylation, histone modifications and regulation of gene expression posttranscriptionally by small, non-coding RNA molecules. Epigenetic modifications play essential roles in the regulation of gene expression and are important in mammalian development and disease processes.

In this study aim to examine whether Gα12 signaling pathway regulates epigenetic modification and to evaluate this change has any physiological meaning.

In Part Ⅰ, we investigated Gα12 action on apoptosis which is mediated by epigenetic modification of XAF1 promoter in NSCLCs. Basal XAF1 mRNA level was very weakly detected in NSCLCs. However, XAF1 expression was restored in A549 cells when blocked Gα12 signal. According to data from MSP and MeDIP, XAF1 promoter methylation was reduced by siGα12. In our data shown that siGα12 was enhanced demethylation of XAF1 promoter and was induced apoptosis.

In Part Ⅱ, we aimed to investigate the effect of Gα12 on cellular proliferation and its underlying mechanism in HepG2 human hepatoma cells. p16 expression was significantly enhanced in HepG2 cells after siGα12 transfection. From MSP, MeDIP and DNMT1 expression data, we can show that Gα12 regulates p16 expression by epigenetic modification mechanism, by inducing DNMT1 expression and activation. Therefore, Gα12 siRNA inhibits the proliferation of HepG2 cells by upregulating p16 expression, suggesting that the abnormal proliferation of HepG2 cells might be resulted from Gα12 signaling to suppress p16 expression of HepG2 hepatoma cells.

In part Ⅲ, we aimed to investigate the role of Gα12 in serum withdrawal -induced apoptosis of HUVECs, and its underlying mechanisms. Gα12 siRNA markedly increased the serum deprivation-induced apoptosis of HUVECs. Because miR-155 has been reported to regulate apoptosis of HUVECs, we examined apoptotic effect of Gα12 on the miR-155 expression. Results indicated that Gα12 regulates the apoptosis of vascular endothelial cells by regulating miR-155 expression. These results suggest that Gα12 protects vascular endothelial cells against vascular injuries causing endothelial dysfunction by regulating miR-155 expression.

From these results, we conclude that Gα12 regulates epigenetic modification in cancer cell and vascular endothelial cells.
Files in This Item:
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 3. Dissertation
Yonsei Authors
Lee, Hyun Jung(이현정)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/148738
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