A Pumilio-induced RNA structure switch in p27-3' UTR controls miR-221 and miR-222 accessibility.
Key regulators of 3' untranslated regions (3' UTRs) are microRNAs and RNA-binding proteins (RBPs). The p27 tumour suppressor is highly expressed in quiescent cells, and its downregulation is required for cell cycle entry after growth factor stimulation. Intriguingly, p27 accumulates in quiescent cells despite high levels of its inhibitors miR-221 and miR-222 (Refs 5, 6). Here we show that miR-221 and miR-222 are underactive towards p27-3' UTR in quiescent cells, as a result of target site hindrance. Pumilio-1 (PUM1) is a ubiquitously expressed RBP that was shown to interact with p27-3' UTR. In response to growth factor stimulation, PUM1 is upregulated and phosphorylated for optimal induction of its RNA-binding activity towards the p27-3' UTR. PUM1 binding induces a local change in RNA structure that favours association with miR-221 and miR-222, efficient suppression of p27 expression, and rapid entry to the cell cycle. We have therefore uncovered a novel RBP-induced structural switch modulating microRNA-mediated gene expression regulation.
Kedde
Martijn
M
Division of Gene Regulation, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
van Kouwenhove
Marieke
M
Zwart
Wilbert
W
Oude Vrielink
Joachim A F
JA
Elkon
Ran
R
Agami
Reuven
R
D020413:3' Untranslated Regions / Q000235:genetics*; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D012313:RNA / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D020413:3' Untranslated Regions; D050760:Cyclin-Dependent Kinase Inhibitor p27; D035683:MicroRNAs; D012313:RNA; D016601:RNA-Binding Proteins; C525709:MIR221, human; C525710:MIR222, human; C471242:PUM1 protein, human
Dev Biol. 2007 May 15;305(2):551-63
17412319
Cancer Cell. 2002 Sep;2(3):243-7
12242156
Dev Cell. 2006 Oct;11(4):441-50
17011485
Genome Res. 2002 Jun;12(6):996-1006
12045153
Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13027-32
18723672
PLoS One. 2008 Sep 08;3(9):e3164
18776931
Cell. 2007 Dec 28;131(7):1273-86
18155131
Genome Biol. 2007;8(11):R250
18039369
EMBO J. 2007 Aug 8;26(15):3699-708
17627278
Cell. 2006 Mar 24;124(6):1169-81
16564011
Nature. 1998 Nov 12;396(6707):177-80
9823898
Nucleic Acids Res. 2003 Jul 1;31(13):3429-31
12824340
Science. 1996 Mar 29;271(5257):1861-4
8596954
Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18125-30
17116888
Mol Cell Biol. 2005 Aug;25(16):6937-47
16055707
Cancer Res. 2008 Apr 15;68(8):2773-80
18413744
Cell Cycle. 2008 Apr 1;7(7):899-903
18414021
Nat Rev Genet. 2008 Feb;9(2):102-14
18197166
Mol Cell Biol. 2008 Jun;28(12):4093-103
18411299
Cell. 2006 Nov 3;127(3):635-48
17081983
Cell Cycle. 2008 Aug 15;7(16):2493-9
18719378
J Cell Biol. 2005 Jun 20;169(6):871-84
15967811
Biochim Biophys Acta. 2007 Jun;1775(2):274-82
17189674
Science. 2005 Sep 2;309(5740):1573-6
16081698
Nat Rev Cancer. 2008 Apr;8(4):253-67
18354415