Document Detail


Inhibition of polyadenylation reduces inflammatory gene induction.
MedLine Citation:
PMID:  23118416     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cordycepin (3' deoxyadenosine) has long been used in the study of in vitro assembled polyadenylation complexes, because it terminates the poly(A) tail and arrests the cleavage complex. It is derived from caterpillar fungi, which are highly prized in Chinese traditional medicine. Here we show that cordycepin specifically inhibits the induction of inflammatory mRNAs by cytokines in human airway smooth muscle cells without affecting the expression of control mRNAs. Cordycepin treatment results in shorter poly(A) tails, and a reduction in the efficiency of mRNA cleavage and transcription termination is observed, indicating that the effects of cordycepin on 3' processing in cells are similar to those described in in vitro reactions. For the CCL2 and CXCL1 mRNAs, the effects of cordycepin are post-transcriptional, with the mRNA disappearing during or immediately after nuclear export. In contrast, although the recruitment of RNA polymerase II to the IL8 promoter is also unaffected, the levels of nascent transcript are reduced, indicating a defect in transcription elongation. We show that a reporter construct with 3' sequences from a histone gene is unaffected by cordycepin, while CXCL1 sequences confer cordycepin sensitivity to the reporter, demonstrating that polyadenylation is indeed required for the effect of cordycepin on gene expression. In addition, treatment with another polyadenyation inhibitor and knockdown of poly(A) polymerase α also specifically reduced the induction of inflammatory mRNAs. These data demonstrate that there are differences in the 3' processing of inflammatory and housekeeping genes and identify polyadenylation as a novel target for anti-inflammatory drugs.
Authors:
Alexander Kondrashov; Hedda A Meijer; Adeline Barthet-Barateig; Hannah N Parker; Asma Khurshid; Sarah Tessier; Marie Sicard; Alan J Knox; Linhua Pang; Cornelia H De Moor
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-11-01
Journal Detail:
Title:  RNA (New York, N.Y.)     Volume:  18     ISSN:  1469-9001     ISO Abbreviation:  RNA     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-19     Completed Date:  2013-01-31     Revised Date:  2014-05-08    
Medline Journal Info:
Nlm Unique ID:  9509184     Medline TA:  RNA     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2236-50     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Cell Line
Chemokine CCL2 / genetics
Chemokine CXCL1 / genetics
DNA-Directed RNA Polymerases / metabolism
Deoxyadenosines / pharmacology*
Gene Expression / drug effects*
HeLa Cells
Humans
Inflammation / genetics*,  metabolism,  prevention & control*
Inflammation Mediators / antagonists & inhibitors,  metabolism
Interleukin-8 / genetics
Mice
Myocytes, Smooth Muscle / drug effects,  metabolism
NF-kappa B / metabolism
NIH 3T3 Cells
Polyadenylation / drug effects*
Promoter Regions, Genetic
RNA Stability / drug effects
RNA, Messenger / genetics,  metabolism
Respiratory Muscles / drug effects,  metabolism
Tumor Necrosis Factor-alpha / pharmacology
Grant Support
ID/Acronym/Agency:
BB/G001847/1//Biotechnology and Biological Sciences Research Council; G1001804/1//National Centre for the Replacement, Refinement and Reduction of Animals in Research; WT078227MA//Wellcome Trust
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/CCL2 protein, human; 0/CXCL1 protein, human; 0/Chemokine CCL2; 0/Chemokine CXCL1; 0/Deoxyadenosines; 0/IL8 protein, human; 0/Inflammation Mediators; 0/Interleukin-8; 0/NF-kappa B; 0/RNA, Messenger; 0/Tumor Necrosis Factor-alpha; 73-03-0/cordycepin; EC 2.7.7.6/DNA-Directed RNA Polymerases
Comments/Corrections

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