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Int J Biochem Cell Biol. 2010 Feb;42(2):329-36. doi: 10.1016/j.biocel.2009.11.012. Epub 2009 Nov 30.

Vitamin D receptor deletion leads to reduced level of IkappaBalpha protein through protein translation, protein-protein interaction, and post-translational modification.

Author information

1
Department of Medicine, Gastroenterology & Hepatology Division, University of Rochester, 601 Elmwood Ave., Rochester, NY 14642, USA.

Abstract

Vitamin D receptor plays an essential role in the regulation of inflammation. Previous studies demonstrate that vitamin D receptor negatively modulates the proinflammatory NF-kappaB pathway. However, it is unknown how vitamin D receptor regulates IkappaBalpha, the endogenous inhibitor of NF-kappaB. Here we investigated the molecular mechanism of vitamin D receptor deletion and IkappaBalpha expression. We found that cells lacking vitamin D receptor had significantly increased levels of IkappaBalpha mRNA and simultaneously decreased levels of IkappaBalpha protein. Lacking vitamin D receptor abolished its binding to the IkappaBalpha promoter. Moreover, the levels of protein translation regulators and the rate of protein synthesis were both decreased in cells lacking vitamin D receptor. At the post-translational level, IkappaBalpha ubiquitination was enhanced, indicating increased degradation of IkappaBalpha in the absence of vitamin D receptor. We further transfected cells with a plasmid carrying either wild-type or mutant IkappaBalpha. The expression of wild-type IkappaBalpha was much higher in the cells with vitamin D receptor than in the cells without vitamin D receptor, whereas the expression of exogenous IkappaBalpha was equally high in both cell lines. In summary, vitamin D receptor deletion affects IkappaBalpha through mRNA transcription, protein translation, protein-protein interaction, post-translational modification, and protein degradation, thus reducing the level of IkappaBalpha protein. Cells lacking vitamin D receptor are known in a proinflammatory state with activation of NF-kappaB. Our study provides new insight into vitamin D receptor regulation of an inhibitor of NF-kappaB in inflammation. Deletion of vitamin D receptor contributes to the activation of NF-kappaB on multiple levels.

PMID:
19931640
PMCID:
PMC2818560
DOI:
10.1016/j.biocel.2009.11.012
[Indexed for MEDLINE]
Free PMC Article

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