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Molecular mechanisms underlying transforming growth factor-beta-induced expression of the apolipoprotein E gene [Abstract]

Singh, Nishi Nihar, Salter, Rebecca Claire and Ramji, Dipak Purshottam 2008. Molecular mechanisms underlying transforming growth factor-beta-induced expression of the apolipoprotein E gene [Abstract]. Atherosclerosis Supplements 9 (1) , p. 21. 10.1016/S1567-5688(08)70078-3

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Abstract

Background and aims: Apolipoprotein E (apoE), a key component of several classes of plasma lipoproteins, has several anti-atherogenic actions, including stimulation of macrophage cholesterol efflux. The objective of this study was to investigate the effects of the anti-atherogenic cytokine, transforming growth factor-beta (TGF-beta), on the expression of apoE in monocytes/macrophages, and to elucidate the underlying regulatory mechanisms. Methods: THP-1 cells were used as a model system with key findings confirmed in primary cultures. The expression of apoE mRNA and protein was investigated by RT-PCR and western blot analysis. Signaling pathways were studied using a combination of pharmacological agents, transfection assays, RNA interference and biochemical analysis. Results: TGF-beta induced the expression of apoE mRNA and protein and this was attenuated by pharmacological inhibitors of c-Jun N-terminal kinase (JNK), p38 kinase and casein kinase 2 (CK2). In support for important roles for these pathways, TGF-beta was found to activate JNK, p38 kinase and CK2. In addition, expression of dominant negative forms of these proteins attenuated the TGF-beta-induced expression of apoE mRNA. TGF-beta also induced the expression of c-Jun, a key downstream target for JNK and member of the activator protein-1 (AP-1) family of transcription factors. Dominant negative c-Jun also inhibited the TGF-beta-induced expression of apoE. Furthermore, TGF-beta induced AP-1 DNA binding and the action of JNK, p38 kinase and CK2 converged on c-Jun/AP-1. Conclusions: These studies suggest potentially novel roles for JNK, p38 kinase, CK2 and c-Jun/AP-1 in the TGF-beta-induced expression of apoE.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Subjects: R Medicine > RC Internal medicine
Additional Information: Abstracts. 77th Congress of the European Atherosclerosis Society, Istanbul, Turkey. Poster sessions
Publisher: Elsevier
ISSN: 1567-5688
Funders: British Heart Foundation
Last Modified: 03 Apr 2018 20:25
URI: http://orca.cf.ac.uk/id/eprint/9269

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