Direct inhibition of the DNA-binding activity of POU transcription factors Pit-1 and Brn-3 by selective binding of a phenyl-furan-benzimidazole dication.
Peixoto, Paul; Liu, Yang; Depauw, Sabineet al.
2008 • In Nucleic Acids Research, 36 (10), p. 3341-53
Direct inhibition of the DNA binding activity of POU transcription factors Pit-1 and Brn-3 by selective binding of a phenyl-furan-benzimidazole dication..pdf
[en] The development of small molecules to control gene expression could be the spearhead of future-targeted therapeutic approaches in multiple pathologies. Among heterocyclic dications developed with this aim, a phenyl-furan-benzimidazole dication DB293 binds AT-rich sites as a monomer and 5'-ATGA sequence as a stacked dimer, both in the minor groove. Here, we used a protein/DNA array approach to evaluate the ability of DB293 to specifically inhibit transcription factors DNA-binding in a single-step, competitive mode. DB293 inhibits two POU-domain transcription factors Pit-1 and Brn-3 but not IRF-1, despite the presence of an ATGA and AT-rich sites within all three consensus sequences. EMSA, DNase I footprinting and surface-plasmon-resonance experiments determined the precise binding site, affinity and stoichiometry of DB293 interaction to the consensus targets. Binding of DB293 occurred as a cooperative dimer on the ATGA part of Brn-3 site but as two monomers on AT-rich sites of IRF-1 sequence. For Pit-1 site, ATGA or AT-rich mutated sequences identified the contribution of both sites for DB293 recognition. In conclusion, DB293 is a strong inhibitor of two POU-domain transcription factors through a cooperative binding to ATGA. These findings are the first to show that heterocyclic dications can inhibit major groove transcription factors and they open the door to the control of transcription factors activity by those compounds.
Direct inhibition of the DNA-binding activity of POU transcription factors Pit-1 and Brn-3 by selective binding of a phenyl-furan-benzimidazole dication.
Uil,T,G., Haisma,H.J. and Rots,M.G. (2003) Therapeutie modulation of endogenous gene function by gents with designed DNA-sequence specificities. Nucleic Acids Res., 31, 6064-6078.
Gniazdowski,M., Denny,W.A., Nelson,S.M. and Czyz,M. (2003) Transcription factors as targets for DNA-interacting drugs. Curr. Med. Chem., 10, 909-924.
Gniazdowski,M., Denny,W.A., Nelson,S.M. and Czyz,M. (2005) Effects of anticancer drugs on transcription factor-DNA interactions. Expert Opin. Ther. Targets, 9, 471-489.
D'Incalci,M., Brunelli,D., Marangon,E., Simone,M., Tavecchio,M., Gescher,A. and Mantovani,R. (2007) Modulation of gene transcription by natural products - a viable anticancer strategy. Curr. Pharm. Des. 13, 2744-2750.
Wemmer,D.E. and Dervan,P.B. (1997) Targeting the minor groove of DNA. Curr. Opin. Struct. Biol., 7, 355-361.
Dervan,P.B. and Edelson,B.S. (2003) Recognition of the DNA minor groove by pyrrole-imidazole polyamides. Curr. Opin. Struct. Biol., 13 284-299.
Melander,C., Burnett,R. and Gottesfeld,J.M. (2004) Regulation of gene expression with pyrrole-imidazole polyamides. J. Biotechnol., 112, 195-220.
Dickinson,L.A., Burnett,R., Melander,C., Edelson,B.S., Arora,P.S., Dervan,P.B. and Gottesfeld,J.M. (2004) Arresting cancer proliferation by small-molecule gene regulation. Chem. Biol., 11, 1583-1594.
Arndt,H.D. and Schoof,S. (2007) Polyamide- and RNA-based activators in living cells: A major step towards controlling gene expression. Chembiochem., 8, 1095-1098.
Nickols,N.G. and Dervan,P.B. (2007) Suppression of androgen receptor-mediated gene-expression by a sequence-specific DNA-binding polyamide. Proc. Natl Acad. Sci. USA, 104, 10418-10423.
Le,N.M., Sielaff,A.M., Cooper,A.J., Mackay,H, Brown,T., Kotecha,M., O'Hare,C., Hochhauser,D., Lee,M. and Hartley,J.A. (2006) Binding of f-PIP, a pyrrole- and imidazole-containing triamide, to the inverted CCAAT box-2 of the topoisomerase IIalpha promoter and modulation of gene expression in cells. Bioorg. Med. Chem. Lett., 16, 6161-6164.
Matsuda,H., Fukuda,N., Ueno,T., Tahira,Y., Ayame,H., Zhang,W., Bando,T., Sugiyama,H., Saito,S., Matsumoto,K. et al. (2006) Development of gene silencing pyrrole-imidazole polyamide targeting the TGF-beta1 promoter for treatment of progressive renal diseases. J. Am. Soc. Nephrol., 17, 422-432.
Olenyuk,B.Z., Zhang,G.J., Klco,J.M., Nickols,N.G., Kaelin,W.G. Jr. and Dervan,P.B. (2004) Inhibition of vascular endothelial growth factor with a sequence-specific hypoxia response element antagonist. Proc. Natl Acad. Sci. USA, 101, 16768-16773.
Nickols,N.G., Jacobs,C.S., Farkas,M.E. and Dervan,P.B. (2007) Improved nuclear localization of DNA-binding polyamides. Nucleic Acids Res. 35, 363-370.
Blume,S.W., Snyder,R.C., Ray,R., Thomas,S., Koller,C.A. and Miller,D.M. (1991) Mithramycin inhibits SP1 binding and selectively inhibits transcriptional activity of the dihydrofolate reductase gene in vitro and in vivo. J. Clin. Invest., 88, 1613-1621.
Lee,T.J., Jung,E.M., Lee,J.T., Kim,S., Park,J.W., Choi,K.S. and Kwon,T.K. (2006) Mithramycin A sensitizes cancer cells to TRAIL-mediated apoptosis by down-regulation of XIAP gene promoter through Sp1 sites. Mol. Cancer Ther., 5, 2737-2746.
Olajide,O.A., Heiss,E.H., Schachner,D., Wright,C.W., Vollmar,A.M. and Dirsch,V.M. (2007) Synthetic cryptolepine inhibits DNA binding of NF-kappaB. Bioorg. Med. Chem., 15, 43-49.
Kong,D., Park,E.J., Stephen,A.G., Calvani,M., Cardellina,J.H., Monks,A., Fisher,R.J., Shoemaker,R.H. and Melillo,G. (2005) Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res., 65, 9047-9055.
Nickols,N.G., Jacobs,C.S., Farkas,M.E. and Dervan,P.B. (2007) Modulating hypoxia-inducible transcription by disrupting the HIF-1-DXA interface. ACS Chem. Biol., 2, 561-571.
Blagburn,B.L., Drain,K.L, Land,T.M., Moore,P.H., Kinard,R.G., Lindsay,D.S., Kumar,A., Shi,J., Boykin,D.W. and Tidwell,R.R. (1998) Dicationic furans inhibit development of Cryptosporidium parvum in HSD/ ICR suckling Swiss mice. J. Parasitol., 84, 851-856.
Wilson,W.D., Nguyen,B., Tanious,F.A., Mathis,A., Hall,J.E., Stephens,C.E. and Boykin,D.W. (2005) Dications that target the DNA minor groove: Compound design and preparation, DNA interactions, cellular distribution and biological activity. Curr. Med. Chem. Anticancer Agents, 5, 389-408.
Bailly,C., Dassonneville,L., Carrasco,C., Lucas,D., Kumar,A., Boykin,D.W. and Wilson,W.D. (1999) Relationships between topoisomerase II inhibition, sequence-specificity and DNA binding mode of dicationic diphenylfuran derivatives. Anticancer Drug Des., 14, 47-60.
Wilson,W.D., Tanious,F., Ding,D., Kumar,A., Boykin,D.W., Colson,P., Houssier,C. and Bailly,C. (1998) Nucleic acid interactions of unfused aromatic cations: Evaluation of proposed minor-groove, major-groove, and intercalation binding modes. J. Am. Chem. Soc., 120, 10310-10321.
Bailly,C., Tardy,C., Wang,L., Armitage,B., Hopkins,K., Kumar,A., Schuster,G.B., Boykin,D.W. and Wilson,W.D. (2001) Recognition of ATGA sequences by the unfused aromatic dication DB293 forming stacked dimers in the DNA minor groove. Biochemistry, 40, 9770-9779.
Wang,L., Bailly,C., Kumar,A., Ding,D., Bajic,M., Boykin,D.W. and Wilson,W. D. (2000) Specific molecular recognition of mixed nucleic acid sequences: An aromatic dication that binds in the DNA minor groove as a dimer. Proc. Natl Acad. Sci. USA, 97, 12-16.
Tanious,F.A., Wilson,W.D., Wang,L., Kumar,A., Boykin,D.W., Marty,C., Baldeyrou,B. and Bailly,C. (2003) Cooperative dimerization of a heterocyclic diamidine determines sequence-specific DNA recognition. Biochemistry, 42, 13576-13586.
Coccia,E.M., Del Russo,N., Stellacci,E., Orsatti,R., Benedetti,E., Marziali,G., Hiscott,J. and Battistini,A. (1999) Activation and repression of the 2-5A synthetase and p21 gene promoters by IRF-1 and IRF-2. Oncogene, 18, 2129-2137.
Garcia,A., Alvarez,C.V., Smith,R. and Dieguez,C. (2001) Regulation of Pit-1 expression by ghrelin and GHRP-6 through the GH secretagogue receptor. Mol. Endocrinol., 15, 1484-1495.
Suaud,L., Formstecher,P. and Laine,B. (1999) The activity of the activation function 2 of the human hepatocyte nuclear factor 4 (HNF-4alpha) is differently modulated by F domains from various origins. Biochem. J., 340, 161-169.
Liu,W., Khare,S.L., Liang,X., Peters,M.A., Liu,X., Cepko,C.L. and Xiang,M. (2000) All Brn3 genes can promote retinal ganglion cell differentiation in the chick. Development, 127, 3237-3247.
Lam,R. and Li,X. (2002) An array-based method for specifically profiling multiple transcription factor activity. Am. Biotechnol. Lab., 8 22-26.
Xiang,M., Zhou,L., Macke,J.P., Yoshioka,T., Hendry,S.H., Eddy,R.L., Shows,T.B. and Nathans,J. (1995) The Brn-3 family of POU-domain factors: primary structure, binding specificity, and expression in subsets of retinal ganglion cells and somatosensory neurons. J. Neurosci., 15, 4762-4785.
Mangalam,H.J., Albert,V.R., Ingraham,H.A., Kapiloff,M., Wilson,L., Nelson,Ch., Elsholtz,H. and Rosenfeld,M.G. (1989) A pituitary POU domain protein, Pit-1, activates both growth hormone and prolactin promoters transcriptionally. Genes Dev., 3, 946-958.
Tanaka,N., Kawakami,T. and Taniguchi,T. (1993) Recognition DNA sequences of interferon regulatory factor 1 (IRF-1) and IRF-2, regulators of cell growth and the interferon system. Mol. Cell. Biol., 13, 4531-4538.
Fraser,J.D., Martinez,V., Straney,R. and Briggs,M.R. (1998) DNA binding and transcription activation specificity of hepatocyte nuclear factor 4. Nucleic Acids Res., 26, 2702-2707.
David-Cordonnier,M.H., Laine,W., Lansiaux,A., Rosu,F., Colson,P., de Pauw,E., Michel,S., Tillequin,F., Koch,M., Hickman,J.A. et al. (2005) Covalent binding of antitumor benzoacronycines to double-stranded DNA induces helix opening and the formation of single-stranded DNA: unique consequences of a novel DNA-bonding mechanism. Mol Cancer Ther., 4, 71-80.
David-Cordonnier,M.-H., Hamdane,M., Bailly,C. and D'Halluin,J.-C. (1998) The DNA binding domain of the human c-Abl tyrosine kinase preferentially binds to DNA sequences containing an AAC-motif and to distorted DNA structures. Biochemistry, 37, 6065-6016.
Munde,M., Ismail,M.A., Arafa,R., Peixoto,P., Collar,C.J., Liu,Y., Hu,L., David-Cordonnier,M.-H., Lansiaux,A., Bailly,C. et al. (2007) Design of DNA minor groove binding diamidines that recognize GC base pair sequences: A novel dimeric-hinge motif. JACS, 129, 13732-13743.
Tanious,F.A., Nguyen,B. and Wilson,W.D. (2008) Biosensor-surface plasmon resonance methods for quantitative analysis of biomolecular interactions. Methods Cell Biol., 84, 53-77.
Lillycrop,K.A., Budrahan,V.S., Lakin,N.D., Terrenghi,G., Wood,J.N., Polak,J.M. and Latchman,D.S. (1992) A novel POU family transcription factor is closely related to Brn-3 but has a distinct expression pattern in neuronal cells. Nucleic Acids Res., 20, 5093-5096.
Ninkina,N.N., Stevens,G.E., Wood,J.N. and Richardson,W.D. (1993) A novel Brn3-like POU transcription factor expressed in subsets of rat sensory and spinal cord neurons. Nucleic Acids Res., 21, 3175-3182.
Jacobson,E.M., Li,P., Leon-del-Rio,A., Rosenfeld,M.G. and Aggarwal,A.K. (1997) Structure of Pit-1 POU domain bound to DNA as a dimer: Unexpected arrangement and flexibility. Genes Dev., 11, 198-212.
Tanious,F.A., Hamelberg,D., Bailly,C., Czarny,A., Boykin,D.W. and Wilson,W.D. (2004) DNA sequence dependent monomer-dimer binding modulation of asymmetric benzimidazole derivatives. J. Am. Chem. Soc. 126, 143-153.
Escalante,C.R., Yie,J., Thanos,D. and Aggarwal,A.K. (1998) Structure of IRF-1 with bound DNA reveals determinants of interferon regulation. Nature, 391, 103-106.
Herr,W. and, Cleary,M.A. (1995) The POU domain: Versatility in transcriptional regulation by a flexible two-in-one DNA-binding domain. Genes Dev., 9, 1679-1693.
Klemm,J.D., Rould,M.A., Aurora,R., Herr,W. and Pabo,C.O. (1994) Crystal structure of the Oct-1 POU domain bound to an actamer site: DNA recognition with tethered DNA-binding modules. Cell, 77, 21-32.
Scully,K.M., Jacobson,E.M., Jepsen,K., Lunyak,V., Viadiu,H., Carrière,C., Rose,D.W., Hooshmand,F., Aggarwal,A.K. and Rosenfeld,M.G. (2000) Allosteric effects of Pit-1 DNA sites on long-term repression in cell type specification. Science, 290, 1127-1131.
Ndisdang,D., Morris,P.J., Chapman,C., Ho,L., Singer,A. and Latchman,D.S. (1998) The HPV-activating cellular transcription factor Brn-3a is overexpressed in CIN3 cervical lesions. J. Clin. Invest., 101 1687-1692.
Dennis,J.H., Budhram-Mahadeo,V. and Latchman,DS. (2001) The Brn-3b POU family transcription factor regulates the cellular growth, proliferation, and anchorage dependence of MCF7 human breast cancer cells. Oncogene, 20, 4961-4971.
Budhram-Mahadeo,V., Ndisang,D., Ward,T., Weber,B.L. and Latchman,D.S. (1999) The Brn-3b POU family transcription factor represses expression of the BRCA-1 anti-oncogene in breast cancer cells. Oncogene, 18, 6684-6691.
Samady,L., Dennis,J., Budhram-Mahadeo,V. and Latchman,D.S. (2004) Activation of CDK4 gene expression in human breast cancer cells by the Brn-3b POU family transcription factor. Cancer Biol. Ther., 3 317-323.
Li,S., Crenshaw,E.B. 3rd, Rawson,E.J., Simmons,D.M., Swanson,L.W. and Rosenfeld,M.G. (1990) Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature, 347, 528-533.
Castrillo,J.L., Theill,L.E. and Karin,M. (1991) Function of the homeodomain protein GHF1 in pituitary cell proliferation. Science, 253, 197-199.
Asa,S.L., Puy,L.A., Lew,A.M., Sundmark,V.C. and Elsholtz,H.P. (1993) Cell type-specific expression of the pituitary transcription activator pit-1 in the human pituitary and pituitary adenomas. J. Clin. Endocrinol. Metab., 77, 1275-1280.
Pellegrini,I., Barlier,A., Gunz,G., Figarella-Branger.D., Enjalbert,A., Grisoli,F. and Jaquet,P. Pit-1 gene expression in the human pituitary and pituitary adenomas. J. Clin. Endocrinol. Metab., 79, 189-196.
Gil-Puig,C., Seoane,S., Blanco,M., Macia,M., Garcia-Caballero,T., Segura,C. and Perez-Fernandez,R. (2005) Pit-1 is expressed in normal and tumorous human breast and regulates GH secretion and cell proliferation. Eur. J. Endocrinol., 153, 335-344.
