title: Stabilization of the c-myc gene promoter quadruplex by specific ligands' inhibitors of telomerase.
abstract: A parallel G-quadruplex structure was recently identified in the NHE III(1) element of the c-myc gene promoter that functioned as a transcriptional repressor. Different series of telomeric G-quadruplex interacting ligands reported to block telomerase activity were evaluated in a new PCR stop assay on the c-myc quadruplex (Pu22myc). Results indicated that the cationic porphyrin TMPyP4 previously described to stabilize c-myc quadruplex and to cause transcription inhibition efficiently inhibited the assay but with a narrow selectivity when parallel experiments were performed with an oligonucleotide (Pu22mu) containing mutations in the guanine repeat which is unable to form a quadruplex. Other ligands presented potent inhibitory properties with IC(50) in the submicromolar range. 307A, a new 2,6-pyridin-dicarboxamide derivative was found to present the highest selectivity as compared to Pu22mu oligonucleotide (>90-fold). Comparison with telomeric G-quadruplex using TRAP-G4 and PCR stop assays also indicated that ligands 307A, telomestatin, and TMPyP4 are equipotent against both c-myc and telomeric sequences while other ligands displayed some partial selectivity (2- to 6-fold) towards one of these sequences. This work provides evidence that G-quadruplex ligands reported as telomerase inhibitors efficiently stabilized c-myc promoter intramolecular quadruplex and may also potentially be used to inhibit c-myc gene transcription in tumor cells.
authors.affiliation: Laboratoire d'Onco-Pharmacologie, JE 2428, UFR de Pharmacie, Université de Reims Champagne-Ardenne, 51096 Reims, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Lemarteleur
authors.forename: Dennis
authors.initials: D
authors.lastname: Gomez
authors.forename: Rajaa
authors.initials: R
authors.lastname: Paterski
authors.forename: Eliane
authors.initials: E
authors.lastname: Mandine
authors.forename: Patrick
authors.initials: P
authors.lastname: Mailliet
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Riou
mesh_terms: D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000737:chemistry*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry; D004795:Enzyme Stability; D008024:Ligands; D016133:Polymerase Chain Reaction / Q000379:methods*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011806:Quinolinium Compounds / Q000737:chemistry*; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D014157:Transcription Factors / Q000737:chemistry*; D014227:Triazines / Q000737:chemistry*
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C480235:G-quadruplex ligand 12459; D008024:Ligands; C116115:MYCBP protein, human; D011806:Quinolinium Compounds; D014157:Transcription Factors; D014227:Triazines; D019098:Telomerase