HDAC activity is required for p65/RelA-dependent repression of PPARδ-mediated transactivation in human keratinocytes

Lene Aarenstrup; Esben Noerregaard Flindt; Kristian Otkjaer; Morten Kirkegaard; Jens Skorstensgaard Andersen; Karsten Kristiansen

doi:10.1038/sj.jid.5701146

HDAC activity is required for p65/RelA-dependent repression of PPARδ-mediated transactivation in human keratinocytes

Lene Aarenstrup, Esben Noerregaard Flindt, Kristian Otkjaer, Morten Kirkegaard, Jens Skorstensgaard Andersen, Karsten Kristiansen

21 Citations (Scopus)

Abstract

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.Journal of Investigative Dermatology advance online publication, 22 November 2007; doi:10.1038/sj.jid.5701146.

Original language	English
Journal	Journal of Investigative Dermatology
Volume	128
Issue number	5
Pages (from-to)	1095-1106
Number of pages	11
ISSN	0022-202X
DOIs	https://doi.org/10.1038/sj.jid.5701146
Publication status	Published - 2008
Externally published	Yes

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@article{0ccb3360f75411ddbf70000ea68e967b,

title = "HDAC activity is required for p65/RelA-dependent repression of PPARδ-mediated transactivation in human keratinocytes",

abstract = "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.Journal of Investigative Dermatology advance online publication, 22 November 2007; doi:10.1038/sj.jid.5701146.",

author = "Lene Aarenstrup and Flindt, {Esben Noerregaard} and Kristian Otkjaer and Morten Kirkegaard and Andersen, {Jens Skorstensgaard} and Karsten Kristiansen",

note = "Keywords: Adult; Cell Differentiation; Cells, Cultured; Epidermis; Histone Deacetylase 1; Histone Deacetylases; Humans; Immunoprecipitation; Keratinocytes; PPAR delta; Protein Structure, Tertiary; Transcription Factor RelA; Transcriptional Activation",

year = "2008",

doi = "10.1038/sj.jid.5701146",

language = "English",

volume = "128",

pages = "1095--1106",

journal = "Journal of Investigative Dermatology",

issn = "0022-202X",

publisher = "nature publishing group",

number = "5",

}

TY - JOUR

T1 - HDAC activity is required for p65/RelA-dependent repression of PPARδ-mediated transactivation in human keratinocytes

AU - Aarenstrup, Lene

AU - Flindt, Esben Noerregaard

AU - Otkjaer, Kristian

AU - Kirkegaard, Morten

AU - Andersen, Jens Skorstensgaard

AU - Kristiansen, Karsten

N1 - Keywords: Adult; Cell Differentiation; Cells, Cultured; Epidermis; Histone Deacetylase 1; Histone Deacetylases; Humans; Immunoprecipitation; Keratinocytes; PPAR delta; Protein Structure, Tertiary; Transcription Factor RelA; Transcriptional Activation

PY - 2008

Y1 - 2008

N2 - 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.Journal of Investigative Dermatology advance online publication, 22 November 2007; doi:10.1038/sj.jid.5701146.

AB - 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.Journal of Investigative Dermatology advance online publication, 22 November 2007; doi:10.1038/sj.jid.5701146.

U2 - 10.1038/sj.jid.5701146

DO - 10.1038/sj.jid.5701146

M3 - Journal article

C2 - 18037904

SN - 0022-202X

VL - 128

SP - 1095

EP - 1106

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

IS - 5

ER -

HDAC activity is required for p65/RelA-dependent repression of PPARδ-mediated transactivation in human keratinocytes

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