Next Article in Journal
Synthesis, DNA Binding and Topoisomerase I Inhibition Activity of Thiazacridine and Imidazacridine Derivatives
Next Article in Special Issue
G-Quadruplex Guanosine Gels and Single Walled Carbon Nanotubes
Previous Article in Journal
Synthesis and Biological Activity of 3-[Phenyl(1,3-thiazol-2-yl)-amino]propanoic Acids and Their Derivatives
Previous Article in Special Issue
G-Quadruplexes as Sensing Probes
Molecules 2013, 18(12), 15019-15034; doi:10.3390/molecules181215019
Article

Helping Eve Overcome ADAM: G-Quadruplexes in the ADAM-15 Promoter as New Molecular Targets for Breast Cancer Therapeutics

1
,
1
,
2
 and
2,*
Received: 25 September 2013 / Revised: 25 November 2013 / Accepted: 26 November 2013 / Published: 5 December 2013
(This article belongs to the Special Issue G-Quadruplexes & i-Motif DNA)
Download PDF [742 KB, uploaded 18 June 2014]

Abstract

ADAM-15, with known zymogen, secretase, and disintegrin activities, is a catalytically active member of the ADAM family normally expressed in early embryonic development and aberrantly expressed in various cancers, including breast, prostate and lung. ADAM-15 promotes extracellular shedding of E-cadherin, a soluble ligand for the HER2/neu receptor, leading to activation, increased motility, and proliferation. Targeted downregulation of both ADAM-15 and HER2/neu function synergistically kills breast cancer cells, but to date there are no therapeutic options for decreasing ADAM-15 function or expression. In this vein, we have examined a unique string of guanine-rich DNA within the critical core promoter of ADAM-15. This region of DNA consists of seven contiguous runs of three or more consecutive guanines, which, under superhelical stress, can relax from duplex DNA to form an intrastrand secondary G-quadruplex (G4) structure. Using biophysical and biological techniques, we have examined the G4 formation within the entire and various truncated regions of the ADAM-15 promoter, and demonstrate strong intrastrand G4 formation serving to function as a biological silencer element. Characterization of the predominant G4 species formed within the ADAM-15 promoter will allow for specific drug targeting and stabilization, and the further development of novel, targeted therapeutics.
Keywords: G-quadruplex; ADAM-15; breast cancer G-quadruplex; ADAM-15; breast cancer
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Share & Cite This Article

Further Mendeley | CiteULike
Export to BibTeX |
EndNote
MDPI and ACS Style

Brown, R.V.; Gaerig, V.C.; Simmons, T.; Brooks, T.A. Helping Eve Overcome ADAM: G-Quadruplexes in the ADAM-15 Promoter as New Molecular Targets for Breast Cancer Therapeutics. Molecules 2013, 18, 15019-15034.

View more citation formats

Related Articles

Article Metrics

Comments

Citing Articles

[Return to top]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert