Transforming growth factor-beta-induced expression of the apolipoprotein E gene requires c-Jun N-terminal kinase, p38 kinase, and casein kinase 2.
OBJECTIVE
The cytokine transforming growth factor-beta (TGF-beta) and apolipoprotein E (apoE) play potent antiatherogenic roles. Despite such importance, the mechanisms underlying the regulation of apoE expression by TGF-beta have not been characterized and were therefore investigated.


RESULTS
Using THP-1 cell line as a model system, with key findings confirmed in primary cultures, we show that TGF-beta induces the expression of apoE, and this is prevented by pharmacological inhibitors of c-Jun N-terminal kinase (JNK), p38 kinase, and casein kinase 2 (CK2). In support for an important role for these pathways, TGF-beta activates JNK, p38 kinase, and CK2, and dominant-negative (DN) forms of these proteins inhibit the cytokine-induced apoE expression. TGF-beta also increases the phosphorylation and expression of c-Jun, a downstream target for JNK action and a component of activator protein-1 (AP-1), and DN c-Jun inhibits the induction of apoE expression in response to the cytokine. AP-1 DNA binding was also induced by TGF-beta, and the action of p38 kinase, JNK, and CK2 converged on the activation of c-Jun/AP-1.


CONCLUSIONS
These studies reveal a novel role for JNK, p38 kinase, CK2, and c-Jun/AP-1 in the TGF-beta-induced expression of apoE.
Singh
Nishi N
NN
School of Biosciences, Cardiff University, United Kingdom.
Ramji
Dipak P
DP
D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D047390:Casein Kinase II / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D005799:Genes, Dominant; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D010766:Phosphorylation; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000502:physiology*
D001057:Apolipoproteins E; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D004247:DNA; D047390:Casein Kinase II; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases