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Novel Molecular Targets for kRAS Downregulation: Promoter G-Quadruplexes

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Technical Report,15 Aug 2014,14 Aug 2015

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University of Mississippi University United States

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The overall objective of this project is to characterize the formation and regulation of newly identified, biologically active, higher order DNA structures in the promoter of kRAS, which is a signaling molecule that has been shown to have aberrant activity in over 90 of pancreatic cancers. The higher order DNA structure under examination is a G-quadruplex, capable of forming in guanine-rich DNA regions found in regulatory regions of DNA, such as telomeres, centromeres, 5 UTRs and promoters. Generally these structures function to silence transcription, although each promoter structure requires individual examination for a functional determination. Within the kRAS promoter lies an extensive guanine-rich region of DNA with three separate putative G-quadruplex forming regions, which we have termed near, mid, and far in relation to their proximity to the transcriptional start site. The near region has been previously described, but we have shown it to be biologically inert, in contrast to the more distal mid-G4-forming region. Progress within the funded project, to date, has focused on this newly identified DNA region, and has characterized predominating isoforms under varied physiological conditions Aim 1. Additionally, we have examined the transcriptional regulation of the kRAS promoter, with particular attention to the dynamic structures formed within the mid-G4-forming region, by the transcriptional regulators Sp1, MAZ, and p53 both wild-type and mutant. Cumulatively, findings from this proposal will have described a novel molecular target with detailed structural and regulatory information, enabling a concentrated drug discovery program with marked promise for new pancreatic cancer therapeutics.

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