Glucocorticoid-mediated repression of the oncogenic microRNA cluster miR-17~92 contributes to the induction of Bim and initiation of apoptosis.
Synthetic glucocorticoids were one of the first effective treatments for lymphoid malignancies because of their ability to induce apoptosis and are still used in combination with other chemotherapeutic agents. Up-regulation of Bim, a proapoptotic member of the B-cell lymphoma-2 family, is an important mediator of glucocorticoid-induced apoptosis. Although glucocorticoids are known to elevate Bim mRNA and protein, little is known about the mechanism. Here, we report that glucocorticoids repress the expression of the microRNA cluster miR-17∼92, which results in elevated Bim protein expression as a mechanism by which glucocorticoids induce Bim. Using a luciferase-Bim 3' untranslated region construct, we demonstrate that glucocorticoids mediate Bim induction posttranscriptionally after miR-17∼92 repression, resulting in increased Bim protein expression. Overexpression of miR-17∼92 microRNAs decreases Bim induction and attenuates glucocorticoid-mediated apoptosis. Conversely, knockdown of miR-17∼92 increases Bim protein expression and glucocorticoid-mediated apoptosis. These findings indicate that endogenous levels of miR-17∼92 repress Bim expression in T-cell lymphoid malignancies and that glucocorticoids induce Bim expression via down-regulation of the miR-17∼92 microRNA cluster. Our findings present a novel mechanism that contributes to the up-regulation of Bim and induction of apoptosis in lymphocytes after glucocorticoid treatment. Furthermore, our work demonstrating that inhibition of miR-17∼92 increases glucocorticoid-induced apoptosis highlights the potential importance of miR-17∼92 as a therapeutic target in leukemias and lymphomas.
Department of Medicine, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Jason K
JK
Molitoris
Karen S
KS
McColl
Clark W
CW
Distelhorst
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D005938:Glucocorticoids; D008565:Membrane Proteins; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins
Cell. 2009 Feb 20;136(4):642-55
19239886
Recent Prog Horm Res. 2003;58:175-97
12795419
Science. 1999 Nov 26;286(5445):1735-8
10576740
Blood. 2005 Dec 15;106(13):4131-8
16118324
Nat Rev Immunol. 2005 Mar;5(3):189-200
15719025
Cell. 2003 Dec 26;115(7):787-98
14697198
EMBO J. 1998 Jan 15;17(2):384-95
9430630
Nat Genet. 2005 May;37(5):495-500
15806104
Cell. 2007 Jun 29;129(7):1337-49
17604722
Mol Cell. 2009 Jan 16;33(1):109-16
19150432
Cancer Cell. 2002 Sep;2(3):183-92
12242151
Oncogene. 2003 Nov 24;22(53):8590-607
14634621
J Biol Chem. 2003 May 23;278(21):18811-6
12646560
Neuron. 2001 Mar;29(3):629-43
11301023
Mol Cell. 2007 Jan 12;25(1):99-112
17218274
Nat Immunol. 2008 Apr;9(4):405-14
18327259
Blood. 2005 Mar 15;105(6):2519-26
15572593
Mol Cell Biol. 2001 Feb;21(3):854-64
11154272
Nature. 2005 Jun 9;435(7043):828-33
15944707
Curr Biol. 2000 Oct 5;10(19):1201-4
11050388
PLoS One. 2008 May 21;3(5):e2236
18493594
Recent Prog Horm Res. 1996;51:457-90; discussion 490-1
8701091
Adv Exp Med Biol. 1999;457:593-605
10500839
Cell. 2008 Mar 7;132(5):875-86
18329372
Mol Cell. 2010 Feb 12;37(3):299-310
20159550
Science. 2007 Jan 5;315(5808):97-100
17204650
Nat Genet. 2006 Sep;38(9):1060-5
16878133
Cell. 1974 Aug;2(4):213-20
4472165
N Engl J Med. 2005 Oct 20;353(16):1711-23
16236742
Pharm Res. 2010 Sep;27(9):1788-99
20424893
J Biol Chem. 2010 Nov 19;285(47):36698-708
20847043
Cancer Res. 2004 May 1;64(9):3087-95
15126345
Cell Death Differ. 2004 Jul;11 Suppl 1:S45-55
15243581
J Biol Chem. 2003 Dec 12;278(50):49795-805
14527951
Cell Death Differ. 2002 Jan;9(1):6-19
11803370
Genomics. 2003 Jun;81(6):543-55
12782123
J Biol Chem. 2007 Jan 26;282(4):2135-43
17135249
J Biol Chem. 2006 Jan 13;281(2):813-23
16282323
Nat Rev Mol Cell Biol. 2008 Jan;9(1):47-59
18097445
J Steroid Biochem Mol Biol. 2000 Jul-Aug;73(5):195-202
11070348
Nature. 2005 Jun 9;435(7043):839-43
15944709
Leukemia. 2009 Apr;23(4):746-52
19148136
J Biol Chem. 2004 May 14;279(20):20858-65
14996839
J Biol Chem. 2003 Jun 27;278(26):23861-7
12676946
Nat Rev Genet. 2008 Feb;9(2):102-14
18197166
EMBO J. 2007 Jun 20;26(12):2856-67
17525735
J Biol Chem. 2004 Dec 31;279(53):55809-17
15509554
Oncogene. 2005 Mar 31;24(14):2317-29
15688014
Cell. 2009 Jun 12;137(6):1005-17
19524505
J Biol Chem. 1991 Oct 5;266(28):18423-6
1917967
Nat Cell Biol. 2010 Apr;12(4):372-9
20190740
Cell. 2008 Apr 18;133(2):217-22
18423194
Adv Exp Med Biol. 1999;457:607-14
10500840