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The interplay between NF-kappaB and E2F1 coordinately regulates inflammation and metabolism in human cardiac cells.

ABSTRACT: Pyruvate dehydrogenase kinase 4 (PDK4) inhibition by nuclear factor-?B (NF-?B) is related to a shift towards increased glycolysis during cardiac pathological processes such as cardiac hypertrophy and heart failure. The transcription factors estrogen-related receptor-? (ERR?) and peroxisome proliferator-activated receptor (PPAR) regulate PDK4 expression through the potent transcriptional coactivator PPAR? coactivator-1? (PGC-1?). NF-?B activation in AC16 cardiac cells inhibit ERR? and PPAR?/? transcriptional activity, resulting in reduced PGC-1? and PDK4 expression, and an enhanced glucose oxidation rate. However, addition of the NF-?B inhibitor parthenolide to these cells prevents the downregulation of PDK4 expression but not ERR? and PPAR?/? DNA binding activity, thus suggesting that additional transcription factors are regulating PDK4. Interestingly, a recent study has demonstrated that the transcription factor E2F1, which is crucial for cell cycle control, may regulate PDK4 expression. Given that NF-?B may antagonize the transcriptional activity of E2F1 in cardiac myocytes, we sought to study whether inflammatory processes driven by NF-?B can downregulate PDK4 expression in human cardiac AC16 cells through E2F1 inhibition. Protein coimmunoprecipitation indicated that PDK4 downregulation entailed enhanced physical interaction between the p65 subunit of NF-?B and E2F1. Chromatin immunoprecipitation analyses demonstrated that p65 translocation into the nucleus prevented the recruitment of E2F1 to the PDK4 promoter and its subsequent E2F1-dependent gene transcription. Interestingly, the NF-?B inhibitor parthenolide prevented the inhibition of E2F1, while E2F1 overexpression reduced interleukin expression in stimulated cardiac cells. Based on these findings, we propose that NF-?B acts as a molecular switch that regulates E2F1-dependent PDK4 gene transcription.

SUBMITTER: Palomer X

PROVIDER: S-EPMC3100304 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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The interplay between NF-kappaB and E2F1 coordinately regulates inflammation and metabolism in human cardiac cells.

Palomer Xavier X Álvarez-Guardia David D Davidson Mercy M MM Chan Tung O TO Feldman Arthur M AM Vázquez-Carrera Manuel M

PloS one 20110523 5

Pyruvate dehydrogenase kinase 4 (PDK4) inhibition by nuclear factor-κB (NF-κB) is related to a shift towards increased glycolysis during cardiac pathological processes such as cardiac hypertrophy and heart failure. The transcription factors estrogen-related receptor-α (ERRα) and peroxisome proliferator-activated receptor (PPAR) regulate PDK4 expression through the potent transcriptional coactivator PPARγ coactivator-1α (PGC-1α). NF-κB activation in AC16 cardiac cells inhibit ERRα and PPARβ/δ tra ...[more]

PMID: 21625432

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Project description:NF?B signaling is of paramount importance in the regulation of apoptosis, proliferation, and inflammatory responses during human development and homeostasis, as well as in many human cancers. Receptor Tyrosine Kinases (RTKs), including the Fibroblast Growth Factor Receptors (FGFRs) are also important in development and disease. However, a direct relationship between growth factor signaling pathways and NF?B activation has not been previously described, although FGFs have been known to antagonize TNF?-induced apoptosis.Here, we demonstrate an interaction between FGFR4 and IKK? (Inhibitor of NF?B Kinase ? subunit), an essential component in the NF?B pathway. This novel interaction was identified utilizing a yeast two-hybrid screen [1] and confirmed by coimmunoprecipitation and mass spectrometry analysis. We demonstrate tyrosine phosphorylation of IKK? in the presence of activated FGFR4, but not kinase-dead FGFR4. Following stimulation by TNF? (Tumor Necrosis Factor ?) to activate NF?B pathways, FGFR4 activation results in significant inhibition of NF?B signaling as measured by decreased nuclear NF?B localization, by reduced NF?B transcriptional activation in electophoretic mobility shift assays, and by inhibition of IKK? kinase activity towards the substrate GST-I?B? in in vitro assays. FGF19 stimulation of endogenous FGFR4 in TNF?-treated DU145 prostate cancer cells also leads to a decrease in IKK? activity, concomitant reduction in NF?B nuclear localization, and reduced apoptosis. Microarray analysis demonstrates that FGF19 + TNF? treatment of DU145 cells, in comparison with TNF? alone, favors proliferative genes while downregulating genes involved in apoptotic responses and NF?B signaling.These results identify a compelling link between FGFR4 signaling and the NF?B pathway, and reveal that FGFR4 activation leads to a negative effect on NF?B signaling including an inhibitory effect on proapoptotic signaling. We anticipate that this interaction between an RTK and a component of NF?B signaling will not be limited to FGFR4 alone.

Dataset Information

The interplay between NF-kappaB and E2F1 coordinately regulates inflammation and metabolism in human cardiac cells.

Publications

The interplay between NF-kappaB and E2F1 coordinately regulates inflammation and metabolism in human cardiac cells.

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