Posttranslational modification of the AU-rich element binding protein HuR by protein kinase Cdelta elicits angiotensin II-induced stabilization and nuclear export of cyclooxygenase 2 mRNA

Doller, Anke; Akool, El-Sayed; Huwiler, Andrea; Müller, Roswitha; Radeke, Heinfried H; Pfeilschifter, Josef; Eberhardt, Wolfgang (2008). Posttranslational modification of the AU-rich element binding protein HuR by protein kinase Cdelta elicits angiotensin II-induced stabilization and nuclear export of cyclooxygenase 2 mRNA. Molecular and cellular biology, 28(8), pp. 2608-25. Washington, D.C.: American Society for Microbiology 10.1128/MCB.01530-07

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The mRNA stabilizing factor HuR is involved in the posttranscriptional regulation of many genes, including that coding for cyclooxygenase 2 (COX-2). Employing RNA interference technology and actinomycin D experiments, we demonstrate that in human mesangial cells (hMC) the amplification of cytokine-induced COX-2 by angiotensin II (AngII) occurs via a HuR-mediated increase of mRNA stability. Using COX-2 promoter constructs with different portions of the 3' untranslated region of COX-2, we found that the increase in COX-2 mRNA stability is attributable to a distal class III type of AU-rich element (ARE). Likewise, the RNA immunoprecipitation assay showed AngII-induced binding of HuR to this ARE. Using the RNA pulldown assay, we demonstrate that the AngII-caused HuR assembly with COX-2 mRNA is found in free and cytoskeleton-bound polysomes indicative of an active RNP complex. Mechanistically, the increased HuR binding to COX-2-ARE by AngII is accompanied by increased nucleocytoplasmic HuR shuttling and depends on protein kinase Cdelta (PKCdelta), which physically interacts with nuclear HuR, thereby promoting its phosphorylation. Mapping of phosphorylation sites identified serines 221 and 318 as critical target sites for PKCdelta-triggered HuR phosphorylation and AngII-induced HuR export to the cytoplasm. Posttranslational modification of HuR by PKCdelta represents an important novel mode of HuR activation implied in renal COX-2 regulation.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology
UniBE Contributor:	Huwiler, Andrea
ISSN:	0270-7306
ISBN:	18285462
Publisher:	American Society for Microbiology
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 15:03
Last Modified:	05 Dec 2022 14:19
Publisher DOI:	10.1128/MCB.01530-07
PubMed ID:	18285462
Web of Science ID:	000254708500011
URI:	https://boris.unibe.ch/id/eprint/27525 (FactScience: 108726)