1: Mol Cell Biol. 2005 Jul;25(14):5893-903. 

Tumor necrosis factor alpha-mediated reduction of KLF2 is due to inhibition of
MEF2 by NF-kappaB and histone deacetylases.

Kumar A, Lin Z, SenBanerjee S, Jain MK.

Program in Cardiovascular Transcriptional Biology, Cardiovascular Division,
Brigham and Women's Hospital, Harvard Medical School, 75 Francis St. TH1127,
Boston, Massachusetts 02115, USA.

Activation of the endothelium by inflammatory cytokines is a key event in the
pathogenesis of vascular disease states. Proinflammatory cytokines repress the
expression of KLF2, a recently identified transcriptional inhibitor of the
cytokine-mediated activation of endothelial cells. In this study the molecular
basis for the cytokine-mediated inhibition of KLF2 is elucidated. Tumor necrosis
factor alpha (TNF-alpha) potently inhibited KLF2 expression. This effect was
completely abrogated by a constitutively active form of IkappaBalpha, as well as
treatment with trichostatin A, implicating a role for the NF-kappaB pathway and
histone deacetylases. Overexpression studies coupled with observations with
p50/p65 null cells support an essential role for p65. A combination of promoter
deletion and mutational analyses, chromatin immunoprecipitation assays, and
co-immunoprecipitation studies indicates that p65 and histone deacetylases 4
cooperate to inhibit the ability of MEF2 factors to induce the KLF2 promoter.
These studies identify a novel mechanism by which TNF-alpha can inhibit
endothelial gene expression. Furthermore, the inhibition of MEF2 function by p65
and HDAC4 has implications for other cellular systems where these factors are
operative.

PMID: 15988006 [PubMed - indexed for MEDLINE]


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