Abstract
Mammalian long intergenic noncoding RNAs (lincRNAs) are best known for modulating transcription. Here we report a posttranscriptional function for lincRNA-p21 as a modulator of translation. Association of the RNA-binding protein HuR with lincRNA-p21 favored the recruitment of let-7/Ago2 to lincRNA-p21, leading to lower lincRNA-p21 stability. Under reduced HuR levels, lincRNA-p21 accumulated in human cervical carcinoma HeLa cells, increasing its association with JUNB and CTNNB1 mRNAs and selectively lowering their translation. With elevated HuR, lincRNA-p21 levels declined, which in turn derepressed JunB and β-catenin translation and increased the levels of these proteins. We propose that HuR controls translation of a subset of target mRNAs by influencing lincRNA-p21 levels. Our findings uncover a role for lincRNA as a posttranscriptional inhibitor of translation.
MeSH Terms
Base Sequence
Carboxypeptidases/genetics,metabolism
ELAV Proteins/genetics,metabolism
HeLa Cells
Humans
MicroRNAs/genetics
Molecular Sequence Data
Protein Biosynthesis
Proteolysis
RNA Processing, Post-Transcriptional
RNA, Long Noncoding/genetics
RNA, Messenger/genetics
RNA-Binding Proteins/genetics,metabolism
Transcription, Genetic
Tumor Cells, Cultured
beta Catenin/genetics,metabolism
Chemicals
CTNNB1 protein, human
ELAV Proteins
MicroRNAs
RNA, Long Noncoding
RNA, Messenger
RNA-Binding Proteins
beta Catenin
mirnlet7 microRNA, human
Carboxypeptidases
SCPEP1 protein, human
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Yoon Je-Hyun
Laboratory of Molecular Biology and Immunology, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
Abdelmohsen Kotb
Srikantan Subramanya
Yang Xiaoling
Martindale Jennifer L
De Supriyo
Huarte Maite
Zhan Ming
Becker Kevin G
Gorospe Myriam
References (29)
29 references, click to expand
-
Molecular mechanisms of long noncoding RNAs.
Mol Cell. 2011 Sep 16;43(6):904-14
PMID: 21925379
-
Long noncoding RNAs and human disease.
Trends Cell Biol. 2011 Jun;21(6):354-61
PMID: 21550244
-
A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response.
Cell. 2010 Aug 6;142(3):409-19
PMID: 20673990
-
Translation repression in human cells by microRNA-induced gene silencing requires RCK/p54.
PLoS Biol. 2006 Jul;4(7):e210
PMID: 16756390
-
Mammalian microRNAs predominantly act to decrease target mRNA levels.
Nature. 2010 Aug 12;466(7308):835-40
PMID: 20703300
-
Relief of microRNA-mediated translational repression in human cells subjected to stress.
Cell. 2006 Jun 16;125(6):1111-24
PMID: 16777601
-
AP-1--The Jun proteins: Oncogenes or tumor suppressors in disguise?
Cell Signal. 2010 Jun;22(6):894-9
PMID: 20060892
-
Localization of ASH1 mRNA particles in living yeast.
Mol Cell. 1998 Oct;2(4):437-45
PMID: 9809065
-
β-catenin as a potential key target for tumor suppression.
Int J Cancer. 2011 Oct 1;129(7):1541-51
PMID: 21455986
-
Posttranscriptional regulation of cancer traits by HuR.
Wiley Interdiscip Rev RNA. 2010 Sep-Oct;1(2):214-29
PMID: 21935886
-
Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability.
Mol Cell. 2011 Aug 5;43(3):327-39
PMID: 21723170
-
Transcriptome-wide analysis of regulatory interactions of the RNA-binding protein HuR.
Mol Cell. 2011 Aug 5;43(3):340-52
PMID: 21723171
-
Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs.
EMBO J. 2004 Aug 4;23(15):3092-102
PMID: 15257295
-
hnRNP C promotes APP translation by competing with FMRP for APP mRNA recruitment to P bodies.
Nat Struct Mol Biol. 2010 Jun;17(6):732-9
PMID: 20473314
-
Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase.
Nat Med. 2008 Jul;14(7):723-30
PMID: 18587408
-
Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses.
Genes Dev. 2011 Sep 15;25(18):1915-27
PMID: 21890647
-
Phosphorylation of HuR by Chk2 regulates SIRT1 expression.
Mol Cell. 2007 Feb 23;25(4):543-57
PMID: 17317627
-
A dicer-independent miRNA biogenesis pathway that requires Ago catalysis.
Nature. 2010 Jun 3;465(7298):584-9
PMID: 20424607
-
Xp54 and related (DDX6-like) RNA helicases: roles in messenger RNP assembly, translation regulation and RNA degradation.
Nucleic Acids Res. 2006 Jun 12;34(10):3082-94
PMID: 16769775
-
Capture of microRNA-bound mRNAs identifies the tumor suppressor miR-34a as a regulator of growth factor signaling.
PLoS Genet. 2011 Nov;7(11):e1002363
PMID: 22102825
-
Mechanisms of miRNA-mediated post-transcriptional regulation in animal cells.
Curr Opin Cell Biol. 2009 Jun;21(3):452-60
PMID: 19450959
-
lncRNAs transactivate STAU1-mediated mRNA decay by duplexing with 3' UTRs via Alu elements.
Nature. 2011 Feb 10;470(7333):284-8
PMID: 21307942
-
Role of the RNA-binding protein HuR in colon carcinogenesis.
Oncogene. 2003 Oct 16;22(46):7146-54
PMID: 14562043
-
MicroRNAs: target recognition and regulatory functions.
Cell. 2009 Jan 23;136(2):215-33
PMID: 19167326
-
Diverse molecular functions of Hu proteins.
Cell Mol Life Sci. 2008 Oct;65(20):3168-81
PMID: 18581050
-
The mRNA binding proteins HuR and tristetraprolin regulate cyclooxygenase 2 expression during colon carcinogenesis.
Gastroenterology. 2009 May;136(5):1669-79
PMID: 19208339
-
The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation.
Mol Cell. 2010 Sep 24;39(6):925-38
PMID: 20797886
-
The RNA-binding protein Elavl1/HuR is essential for placental branching morphogenesis and embryonic development.
Mol Cell Biol. 2009 May;29(10):2762-76
PMID: 19307312
-
HuR recruits let-7/RISC to repress c-Myc expression.
Genes Dev. 2009 Aug 1;23(15):1743-8
PMID: 19574298