HDAC activity is required for p65/RelA-dependent repression of PPARdelta-mediated transactivation in human keratinocytes.
Peroxisome proliferator-activated receptors (PPARs) play a key role in differentiation, inflammation, migration, and survival of epidermal keratinocytes. The NF-kappaB has long been known to play pivotal roles in immune and inflammatory responses, and furthermore NF-kappaB has been implicated in the regulation of epidermal homeostasis. Recent studies have established that p65/RelA is a potent repressor of PPARdelta-mediated transactivation in human keratinocytes. In this article we further investigate the molecular mechanisms dictating the NF-kappaB-dependent repression of PPARdelta in human keratinocytes. We demonstrate that repression is unique to p65/RelA, as no other member of the NF-kappaB family had an impact on PPARdelta-mediated transactivation. Interestingly, our results show that p65/RelA only represses PPARdelta-dependent transactivation when PPARdelta is bound to DNA via its DNA-binding domain. We show that repression is sensitive to inhibition of histone deacetylases (HDACs) by tricostatin A (TSA), suggesting that HDAC activity is indispensable for p65/RelA-mediated repression. Accordingly, we demonstrate that a ternary complex consisting of PPARdelta, p65/RelA, and HDAC1 is formed in vivo. Finally, we demonstrate that TSA relieves tumor necrosis factor-alpha (TNFalpha)-induced repression of PPARdelta-mediated transactivation of the PPARdelta target gene adipose differentiation-related protein (ADRP) indicating that cross-talk between PPARdelta and NF-kappaB is of biological significance in human keratinocytes.
Aarenstrup
Lene
L
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
Flindt
Esben Noerregaard
EN
Otkjaer
Kristian
K
Kirkegaard
Morten
M
Andersen
Jens Skorstensgaard
JS
Kristiansen
Karsten
K
D000328:Adult; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D000078404:Epidermal Cells; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology*; D047494:PPAR delta / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051996:Transcription Factor RelA / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology
D047494:PPAR delta; D051996:Transcription Factor RelA; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases