Targeting the Promoter Regions of Pdgf Ligand and Receptor.

Author:   Yong Qin
Publisher:   Proquest, Umi Dissertation Publishing
ISBN:  

9781243485182


Pages:   238
Publication Date:   02 September 2011
Format:   Paperback
Availability:   Not yet available   Availability explained
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Targeting the Promoter Regions of Pdgf Ligand and Receptor.


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Overview

Aberrant expression of Platelet-derived growth factor A (PDGF-A) and PDGF receptor-beta (PDGFR-beta) play critical roles in the angiogenesis and proliferation of several malignancies. In this dissertation I explore the transcriptional regulatory role of the G-quadruplex-forming regions in the promoters of human PDGF-A and PDGFR-beta, and identify new targets for developing small molecules to modulate their expression in tumors. For PDGF-A promoter, our studies focus on two essential nuclease hypersensitive elements, NHEPDGF-A and 5'-end far upstream 5'-SHS. The structural aspects of the intramolecular G-quadruplexes formed in NHEPDGF-A and the ligands to stabilize these secondary DNA structures have been investigated by using single-stranded and duplex DNA of the NHEPDGF-A. We demonstrate that the G-quadruplex-interactive compound, TMPyP4, can selectively inhibit the basal promoter activity of PDGF-A, suggesting that the NHEPDGF-A G-quadruplex acts as a repressor in PDGF-A transcription. We also found that the 5'-SHS G-rich strand oligomer can invade the NHEPDGF-A and form a unique three-stranded complex in supercoiled plasmids, which is facilitated by potassium ions and TMPyP4. Therefore, we propose a novel molecular mechanism for transcriptional silencing of the NHEPDGF-A by 5'-SHS in the PDGF-A promoter, in that the formation of G-quadruplex in the NHE PDGF-A provides a platform for the G-rich strand of 5'-SHS to invade and form a partial duplex DNA with the C-rich strand of the NHEPDGF-A, resulting in displacement of hnRNP K and thus transcription silencing. Prior to the studies describe here, the promoter of human PDGFR-beta had not been identified. Herein, we have cloned and characterized the first functional promoter of human PDGFR-beta gene. A crucial highly GC-rich region (NHE PDGFR-beta) in the human PDGFR-beta promoter has been identified by its hypersensitivity to the S1 nuclease. Further studies demonstrate that stable G-quadruplex structures can form in the G-rich strand of NHEPDGFR-beta . The G-quadruplex-interactive molecule, telomestatin, can selectively stabilize G-quadruplexes formed in the human PDGFR-beta promoter and inhibit its expression in Daoy cells. On the basis of these results, we propose that ligand-mediated stabilization of the G-quadruplex structure in the proximal promoter region of human PDGF-A or PDGFR-beta can be used to modulate the expression of these proto-oncogenes.

Full Product Details

Author:   Yong Qin
Publisher:   Proquest, Umi Dissertation Publishing
Imprint:   Proquest, Umi Dissertation Publishing
Dimensions:   Width: 20.30cm , Height: 1.60cm , Length: 25.40cm
Weight:   0.481kg
ISBN:  

9781243485182


ISBN 10:   1243485183
Pages:   238
Publication Date:   02 September 2011
Audience:   General/trade ,  General
Format:   Paperback
Publisher's Status:   Active
Availability:   Not yet available   Availability explained
This item is yet to be released. You can pre-order this item and we will dispatch it to you upon its release.

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