Drug targeting of the c-MYC promoter to repress gene expression via a G-quadruplex silencer element.
In this review, we describe the evidence for a parallel-stranded G-quadruplex in the purine-rich strand of the nuclease hypersensitivity element III(1) (NHE III(1)) of the promoter of c-MYC upstream of the P1 and P2 promoters. This biologically relevant G-quadruplex is a mixture of four loop isomers. The folding pattern of a nuclear magnetic resonance (NMR)-derived structure for the predominant loop isomer of this G-quadruplex has been obtained. This G-quadruplex has been demonstrated to be a silencer element, and the cationic porphyrin TMPyP4 has been shown to stabilize this G-quadruplex. Furthermore, TMPyP4 has been shown to repress c-MYC expression, and this effect is mediated through the silencer element. Last, the in vivo activity of TMPyP4 in xenograph models is presented.
Hurley
Laurence H
LH
University of Arizona, College of Pharmacy, Tucson, AZ, USA. hurley@pharmacy.arizona.edu
Von Hoff
Daniel D
DD
Siddiqui-Jain
Adam
A
Yang
Danzhou
D
D000818:Animals; D001483:Base Sequence; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020868:Gene Silencing; D016259:Genes, myc / Q000187:drug effects*; D006801:Humans; D007536:Isomerism; D011166:Porphyrins / Q000737:chemistry / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D037941:Silencer Elements, Transcriptional; D014158:Transcription, Genetic
D011166:Porphyrins; D016271:Proto-Oncogene Proteins c-myc; C021096:tetra(4-N-methylpyridyl)porphine