PMID- 23223443
OWN - NLM
STAT- MEDLINE
DCOM- 20130429
LR  - 20211021
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 288
IP  - 7
DP  - 2013 Feb 15
TI  - Antagonistic function of the RNA-binding protein HuR and miR-200b in 
      post-transcriptional regulation of vascular endothelial growth factor-A 
      expression and angiogenesis.
PG  - 4908-21
LID - 10.1074/jbc.M112.423871 [doi]
AB  - HuR, also known as Elavl1, is an RNA-binding protein that regulates embryonic 
      development, progenitor cell survival, and cell stress responses. The role of HuR 
      in angiogenesis is not known. Using a myeloid-specific HuR knock-out mouse model 
      (Elavl1Mo KO), we show that HuR expression in bone marrow-derived macrophages 
      (BMDMs) is needed to maintain the expression of genes enriched in AU-rich 
      elements and U-rich elements in the 3'-UTR. In addition, BMDMs from Elavl1Mo KO 
      mice also showed alterations in expression of several miRNAs. Interestingly, 
      computational analysis suggested that miR-200b, which is up-regulated in Elavl1Mo 
      KO BMDMs, interacts with myeloid mRNAs very close to the HuR binding sites, 
      suggesting competitive regulation of gene expression. One such mRNA encodes 
      vascular endothelial growth factor (VEGF)-A, a major regulator of angiogenesis. 
      Immunoprecipitation of RNA-protein complexes and luciferase reporter assays 
      indicate that HuR antagonizes the suppressive activity of miR-200b, 
      down-regulates miR-200b expression, and promotes VEGF-A expression. Indeed, 
      Vegf-a and other angiogenic regulatory transcripts were down-regulated in 
      Elavl1Mo KO BMDMs. Interestingly, tumor growth, angiogenesis, vascular sprouting, 
      branching, and permeability were significantly attenuated in Elavl1Mo KO mice, 
      suggesting that HuR-regulated myeloid-derived factors modulate tumor angiogenesis 
      in trans. Zebrafish embryos injected with an elavl1 morpholino oligomer or 
      miR-200b mimic showed angiogenesis defects in the subintestinal vein plexus, and 
      elavl1 mRNA rescued the repressive effect of miR-200b. In addition, miR-200b and 
      HuR morpholino oligomer suppressed the activity of a zVEGF 3'-UTR luciferase 
      reporter construct. Together, these studies reveal an evolutionarily conserved 
      post-transcriptional mechanism involving competitive interactions between HuR and 
      miR-200b that controls angiogenesis.
FAU - Chang, Sung-Hee
AU  - Chang SH
AD  - Center for Vascular Biology, Department of Pathology and Laboratory Medicine, 
      Weill Cornell Medical College, Cornell University, New York, New York 10065, USA.
FAU - Lu, Yi-Chien
AU  - Lu YC
FAU - Li, Xi
AU  - Li X
FAU - Hsieh, Wan-Ying
AU  - Hsieh WY
FAU - Xiong, Yuquan
AU  - Xiong Y
FAU - Ghosh, Mallika
AU  - Ghosh M
FAU - Evans, Todd
AU  - Evans T
FAU - Elemento, Olivier
AU  - Elemento O
FAU - Hla, Timothy
AU  - Hla T
LA  - eng
GR  - HL49094/HL/NHLBI NIH HHS/United States
GR  - R01 HL049094/HL/NHLBI NIH HHS/United States
GR  - HL56182/HL/NHLBI NIH HHS/United States
GR  - R01 HL056182/HL/NHLBI NIH HHS/United States
GR  - R01 HL111400/HL/NHLBI NIH HHS/United States
GR  - R37 HL056182/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20121206
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (3' Untranslated Regions)
RN  - 0 (CD11b Antigen)
RN  - 0 (ELAV Proteins)
RN  - 0 (MIRN200 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Mirn200 microRNA, mouse)
RN  - 0 (Vascular Endothelial Growth Factor A)
SB  - IM
MH  - 3' Untranslated Regions
MH  - Amino Acid Sequence
MH  - Animals
MH  - CD11b Antigen/biosynthesis
MH  - ELAV Proteins/*metabolism
MH  - Enzyme-Linked Immunosorbent Assay/methods
MH  - Gene Deletion
MH  - *Gene Expression Regulation, Developmental
MH  - HEK293 Cells
MH  - Humans
MH  - Macrophages/cytology/metabolism
MH  - Mice
MH  - MicroRNAs/*metabolism
MH  - Molecular Sequence Data
MH  - *Neovascularization, Pathologic
MH  - Vascular Endothelial Growth Factor A/*metabolism
MH  - Zebrafish
PMC - PMC3576095
EDAT- 2012/12/12 06:00
MHDA- 2013/04/30 06:00
PMCR- 2014/02/15
CRDT- 2012/12/11 06:00
PHST- 2012/12/11 06:00 [entrez]
PHST- 2012/12/12 06:00 [pubmed]
PHST- 2013/04/30 06:00 [medline]
PHST- 2014/02/15 00:00 [pmc-release]
AID - S0021-9258(20)46293-3 [pii]
AID - M112.423871 [pii]
AID - 10.1074/jbc.M112.423871 [doi]
PST - ppublish
SO  - J Biol Chem. 2013 Feb 15;288(7):4908-21. doi: 10.1074/jbc.M112.423871. Epub 2012 
      Dec 6.