title: Helping Eve overcome ADAM: G-quadruplexes in the ADAM-15 promoter as new molecular targets for breast cancer therapeutics.
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.
authors: College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA. tabrooks@olemiss.edu.
authors: Robert V
authors: RV
authors: Brown
authors: Vanessa C
authors: VC
authors: Gaerig
authors: Taesha
authors: T
authors: Simmons
authors: Tracy A
authors: TA
authors: Brooks
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry* / Q000235:genetics*; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D002460:Cell Line; D002942:Circular Dichroism; D005260:Female; D054856:G-Quadruplexes; D020868:Gene Silencing; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics*; D009154:Mutation; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
chemical_list: D008565:Membrane Proteins; D051722:ADAM Proteins; C098660:ADAM15 protein, human