Repression of the miR-17-92 cluster by p53 has an important function in hypoxia-induced apoptosis.
We here report that miR-17-92 cluster is a novel target for p53-mediated transcriptional repression under hypoxia. We found the expression levels of miR-17-92 cluster were reduced in hypoxia-treated cells containing wild-type p53, but were unchanged in hypoxia-treated p53-deficient cells. The repression of miR-17-92 cluster under hypoxia is independent of c-Myc. Luciferase reporter assays mapped the region responding to p53-mediated repression to a p53-binding site in the proximal region of the miR-17-92 promoter. Chromatin immunoprecipitation (ChIP), Re-ChIP and gel retardation assays revealed that the binding sites for p53- and the TATA-binding protein (TBP) overlap within the miR-17-92 promoter; these proteins were found to compete for binding. Finally, we show that pri-miR-17-92 expression correlated well with p53 status in colorectal carcinomas. Over-express miR-17-92 cluster markedly inhibits hypoxia-induced apoptosis, whereas blocked miR-17-5p and miR-20a sensitize the cells to hypoxia-induced apoptosis. These data indicated that p53-mediated repression of miR-17-92 expression likely has an important function in hypoxia-induced apoptosis, and thus further our understanding of the tumour suppressive function of p53.
Yan
Hong-li
HL
Institute of Genetics, Second Military Medical University, Shanghai, China.
Xue
Geng
G
Mei
Qian
Q
Wang
Yu-zhao
YZ
Ding
Fei-xiang
FX
Liu
Mo-Fang
MF
Lu
Ming-Hua
MH
Tang
Ying
Y
Yu
Hong-yu
HY
Sun
Shu-han
SH
D017209:Apoptosis; D001665:Binding Sites; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D006801:Humans; D000860:Hypoxia; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D005810:Multigene Family; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D008156:Luciferases
Cell Death Differ. 2003 Apr;10(4):404-8
12719716
Mol Cell Biol. 2007 Mar;27(5):1859-67
17194750
Nucleic Acids Res. 2004 Nov 01;32(19):e151
15520460
Science. 1991 Jul 5;253(5015):49-53
1905840
J Biol Chem. 2001 Nov 23;276(47):43604-10
11571296
Clin Cancer Res. 2008 Mar 1;14(5):1340-8
18316553
FEBS Lett. 1997 Apr 14;406(3):234-42
9136893
Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19678-83
19066217
Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11755-60
15284443
Mol Cell Biol. 1994 Apr;14(4):2556-63
8139558
RNA. 2006 May;12(5):913-20
16540696
J Biol Chem. 2007 Jan 26;282(4):2130-4
17135268
Mol Cancer. 2007 Jan 14;6:5
17222355
Nat Immunol. 2008 Apr;9(4):405-14
18327259
Nature. 2005 Jun 9;435(7043):828-33
15944707
BMC Bioinformatics. 2005 Mar 30;6:79
15799782
PLoS One. 2008 May 21;3(5):e2236
18493594
Nat Rev Cancer. 2002 Jan;2(1):38-47
11902584
Cell Death Differ. 2007 Mar;14(3):411-21
16917513
Mutagenesis. 2005 Sep;20(5):365-73
16105905
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61
16461460
Nat Genet. 2006 Sep;38(9):1060-5
16878133
PLoS Genet. 2007 Aug;3(8):e146
17784791
N Engl J Med. 2005 Oct 27;353(17):1793-801
16251535
Oncogene. 2007 Sep 6;26(41):6099-105
17384677
Cell. 2005 Jul 15;122(1):6-7
16009126
Cancer Res. 1994 Sep 15;54(18):4855-78
8069852
Mol Cell Biol. 2006 Oct;26(19):7030-45
16980608
Nature. 2005 Jun 9;435(7043):839-43
15944709
BMC Mol Biol. 2008 Oct 31;9:98
18976469
Nucleic Acids Res. 2005 Mar 01;33(4):1290-7
15741182
Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1931-6
12574499
Oncogene. 2004 Apr 12;23(16):2809-18
15077144
FASEB J. 2004 Dec;18(15):1906-8
15456741
Mol Cell Biol. 2001 Feb;21(4):1297-310
11158315
Nature. 1996 Jan 4;379(6560):88-91
8538748
Cancer Res. 2005 Nov 1;65(21):9628-32
16266980
Mol Cell Biol. 2005 Sep;25(17):7423-31
16107691
Cell. 2003 Dec 26;115(7):787-98
14697198
J Clin Invest. 1999 Aug;104(3):263-9
10430607
Oncogene. 1998 Dec 31;17(26):3401-15
10030664
Methods. 2001 Dec;25(4):402-8
11846609
Genes Dev. 1996 Dec 1;10(23):2971-80
8956998
J Biol Chem. 1999 Mar 19;274(12):8039-45
10075703
J Mol Biol. 2004 May 28;339(2):327-35
15136036
Novartis Found Symp. 2001;240:115-28; discussion 128-32
11727925
J Biol Chem. 1999 Apr 16;274(16):10911-5
10196169
Genes Dev. 2002 Apr 15;16(8):984-93
11959846
Cell. 2004 Jan 23;116(2):281-97
14744438
Cell. 2002 Jul 12;110(1):9-12
12150992
Biochem Biophys Res Commun. 2005 Jun 10;331(3):718-25
15865928
Nat Genet. 1992 Apr;1(1):45-9
1301998
Cancer Sci. 2008 Jun;99(6):1147-54
18429962
J Biol Chem. 2002 Feb 1;277(5):3247-57
11714700
Curr Biol. 2007 Dec 4;17(23):2081-6
18060787