Modulating hypoxia-inducible transcription by disrupting the HIF-1-DNA interface.
Transcription mediated by hypoxia-inducible factor (HIF-1) contributes to tumor angiogenesis and metastasis but is also involved in activation of cell-death pathways and normal physiological processes. Given the complexity of HIF-1 signaling, it could be advantageous to target a subset of HIF-1 effectors rather than the entire pathway. We compare the genome-wide effects of three molecules that each interfere with the HIF-1-DNA interaction: a polyamide targeted to the hypoxia response element, small interfering RNA targeted to HIF-1alpha, and echinomycin, a DNA-binding natural product with a similar but less specific sequence preference than the polyamide. The polyamide affects a subset of hypoxia-induced genes consistent with its binding site preferences. For comparison, HIF-1alpha siRNA and echinomycin each affect the expression of nearly every gene induced by hypoxia. Remarkably, the total number of genes affected by either polyamide or HIF-1alpha siRNA over a range of thresholds is comparable. The data show that polyamides can be used to affect a subset of a pathway regulated by a transcription factor. In addition, this study offers a unique comparison of three complementary approaches towards exogenous control of endogenous gene expression.
Nickols
Nicholas G
NG
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Jacobs
Claire S
CS
Farkas
Michelle E
ME
Dervan
Peter B
PB
D001483:Base Sequence; D016923:Cell Death; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D019802:Succinic Acid / Q000378:metabolism; D014158:Transcription, Genetic
D051793:Hypoxia-Inducible Factor 1; D004247:DNA; D019802:Succinic Acid
J Am Chem Soc. 2003 Jul 16;125(28):8476-85
12848553
Genes Dev. 2000 Aug 15;14(16):1983-91
10950862
Science. 1984 Sep 14;225(4667):1122-7
6089341
Nat Biotechnol. 2002 Feb;20(2):135-41
11821858
Nat Struct Biol. 1998 Feb;5(2):104-9
9461074
Science. 2001 Apr 20;292(5516):464-8
11292862
N Engl J Med. 2007 Jan 11;356(2):115-24
17215529
J Biol Chem. 1999 Aug 20;274(34):24147-52
10446188
Biochemistry. 1992 Nov 17;31(45):10969-75
1445835
Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14628-33
9843940
Nat Rev Cancer. 2003 Oct;3(10):721-32
13130303
Nucleic Acids Res. 1984 Jun 25;12(12):4865-79
6204275
Oncogene. 2003 Jul 24;22(30):4734-44
12879018
Circ Res. 1995 Sep;77(3):638-43
7641334
Nature. 2004 Sep 16;431(7006):338-42
15372040
Mol Cell Biol. 1996 Sep;16(9):4604-13
8756616
Acta Oncol. 2006;45(3):317-24
16644575
Methods Enzymol. 2001;340:450-66
11494863
Invest New Drugs. 1985;3(4):403-10
3910610
Mol Pharmacol. 2004 Dec;66(6):1361-71
15340042
J Biol Chem. 1999 Aug 20;274(34):24142-6
10446187
N Engl J Med. 2005 Dec 8;353(23):2477-90
16339096
Nat Biotechnol. 2003 Jun;21(6):635-7
12754523
Bioorg Med Chem. 2003 Oct 1;11(20):4333-40
13129569
Mol Cancer Res. 2006 Sep;4(9):601-5
16940159
J Biochem. 2004 Sep;136(3):273-7
15598882
Adv Enzyme Regul. 2004;44:75-92
15581484
Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10418-23
17566103
Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4459-64
15753290
Nature. 2004 Sep 16;431(7006):371-8
15372045
Nucleic Acids Res. 2004 Jan 02;32(1):65-72
14704344
Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):12890-5
9789010
Mol Cancer Res. 2004 Feb;2(2):89-95
14985465
Oncogene. 2004 Jul 22;23(33):5624-31
15184875
Nature. 1998 Jan 29;391(6666):468-71
9461213
Biochem J. 2005 Aug 15;390(Pt 1):189-97
15823097
J Biol Chem. 1997 Sep 19;272(38):23659-67
9295307
J Biol Chem. 2004 Dec 17;279(51):53562-70
15466858
N Engl J Med. 2003 Jul 31;349(5):427-34
12890841
Cancer Cell. 2004 Jul;6(1):33-43
15261140
Cancer Lett. 2006 Jun 8;237(1):10-21
16002209
Nature. 1998 Feb 19;391(6669):806-11
9486653
J Biol Chem. 1996 Dec 20;271(51):32529-37
8955077
Proc Natl Acad Sci U S A. 2004 Nov 30;101(48):16768-73
15556999
Biochem Biophys Res Commun. 1998 Apr 28;245(3):894-9
9588211
Nature. 1974 Dec 20;252(5485):653-7
4437614
Curr Opin Struct Biol. 2003 Jun;13(3):284-99
12831879
Nucleic Acids Res. 2007;35(2):363-70
17175539
J Biol Chem. 2001 Apr 6;276(14):11323-34
11145970
Cancer Res. 2005 Oct 1;65(19):9047-55
16204079
Bioorg Med Chem. 2002 Aug;10(8):2767-74
12057666
N Engl J Med. 2007 Jan 11;356(2):125-34
17215530
Angew Chem Int Ed Engl. 2004 Jul 5;43(27):3591-4
15293255
J Biol Chem. 1994 Sep 23;269(38):23757-63
8089148
Nature. 2004 Sep 16;431(7006):343-9
15372041
Nature. 2006 May 25;441(7092):437-43
16724055