Peroxisome proliferator-activated receptor-β/δ inhibits epidermal cell proliferation by down-regulation of kinase activity

Dae J. Kim, Iain A. Murray, Amanda M. Burns, Frank J. Gonzalez, Gary H. Perdew, Jeffrey M. Peters

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Recent work has shown that peroxisome proliferator-activated receptor β (PPARβ) attenuates cell proliferation and skin carcinogenesis, and this is due in part to regulation of ubiquitin C expression. In these studies, the role of PPARβ in modulating ubiquitin-dependent protein kinase Cα (PKCα) levels and phosphorylation signaling pathways was evaluated. Intracellular phosphorylation analysis showed that phosphorylated PKCα and other kinases were lower in wild-type mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) as compared with PPARβ-null mouse skin. No differences in expression levels of other PKC isoforms present in skin were observed. Lower ubiquitination of PKCα was found in TPA-treated PPARβ-null skin as compared with wild-type, and inhibition of ubiquitin-dependent proteasome degradation prevented TPA-induced down-regulation of PKCα. The activity of PKCα and downstream signaling kinases is enhanced, and expression of cyclooxygenase-2 (COX-2) is significantly greater, in PPARβ-null mouse skin in response to TPA compared with wild-type mouse skin. Inhibition of PKCα or COX-2 reduced cell proliferation in TPA-treated PPARβ-null keratinocytes in a dose-dependent manner, whereas it only slightly influenced cell proliferation in wild-type keratinocytes. Combined, these studies provide strong evidence that PPARβ attenuates cell proliferation by modulating PKCα/Raf1/MEK/ERK activity that may be due in part to reduced ubiquitin-dependent turnover of PKCα.

Original languageEnglish (US)
Pages (from-to)9519-9527
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number10
DOIs
StatePublished - Mar 11 2005
Externally publishedYes

Fingerprint

Peroxisome Proliferator-Activated Receptors
Cell proliferation
Protein Kinase C
Phosphotransferases
Down-Regulation
Cell Proliferation
Tetradecanoylphorbol Acetate
Skin
Acetates
Ubiquitin
Phosphorylation
Cyclooxygenase 2
Keratinocytes
Ubiquitin C
Ubiquitination
Mitogen-Activated Protein Kinase Kinases
Proteasome Endopeptidase Complex
Protein Isoforms
Carcinogenesis
Degradation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Peroxisome proliferator-activated receptor-β/δ inhibits epidermal cell proliferation by down-regulation of kinase activity. / Kim, Dae J.; Murray, Iain A.; Burns, Amanda M.; Gonzalez, Frank J.; Perdew, Gary H.; Peters, Jeffrey M.

In: Journal of Biological Chemistry, Vol. 280, No. 10, 11.03.2005, p. 9519-9527.

Research output: Contribution to journalArticle

Kim, Dae J. ; Murray, Iain A. ; Burns, Amanda M. ; Gonzalez, Frank J. ; Perdew, Gary H. ; Peters, Jeffrey M. / Peroxisome proliferator-activated receptor-β/δ inhibits epidermal cell proliferation by down-regulation of kinase activity. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 10. pp. 9519-9527.
@article{e20457b62ef54f39aed522df6f7d52fa,
title = "Peroxisome proliferator-activated receptor-β/δ inhibits epidermal cell proliferation by down-regulation of kinase activity",
abstract = "Recent work has shown that peroxisome proliferator-activated receptor β (PPARβ) attenuates cell proliferation and skin carcinogenesis, and this is due in part to regulation of ubiquitin C expression. In these studies, the role of PPARβ in modulating ubiquitin-dependent protein kinase Cα (PKCα) levels and phosphorylation signaling pathways was evaluated. Intracellular phosphorylation analysis showed that phosphorylated PKCα and other kinases were lower in wild-type mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) as compared with PPARβ-null mouse skin. No differences in expression levels of other PKC isoforms present in skin were observed. Lower ubiquitination of PKCα was found in TPA-treated PPARβ-null skin as compared with wild-type, and inhibition of ubiquitin-dependent proteasome degradation prevented TPA-induced down-regulation of PKCα. The activity of PKCα and downstream signaling kinases is enhanced, and expression of cyclooxygenase-2 (COX-2) is significantly greater, in PPARβ-null mouse skin in response to TPA compared with wild-type mouse skin. Inhibition of PKCα or COX-2 reduced cell proliferation in TPA-treated PPARβ-null keratinocytes in a dose-dependent manner, whereas it only slightly influenced cell proliferation in wild-type keratinocytes. Combined, these studies provide strong evidence that PPARβ attenuates cell proliferation by modulating PKCα/Raf1/MEK/ERK activity that may be due in part to reduced ubiquitin-dependent turnover of PKCα.",
author = "Kim, {Dae J.} and Murray, {Iain A.} and Burns, {Amanda M.} and Gonzalez, {Frank J.} and Perdew, {Gary H.} and Peters, {Jeffrey M.}",
year = "2005",
month = "3",
day = "11",
doi = "10.1074/jbc.M413808200",
language = "English (US)",
volume = "280",
pages = "9519--9527",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "10",

}

TY - JOUR

T1 - Peroxisome proliferator-activated receptor-β/δ inhibits epidermal cell proliferation by down-regulation of kinase activity

AU - Kim, Dae J.

AU - Murray, Iain A.

AU - Burns, Amanda M.

AU - Gonzalez, Frank J.

AU - Perdew, Gary H.

AU - Peters, Jeffrey M.

PY - 2005/3/11

Y1 - 2005/3/11

N2 - Recent work has shown that peroxisome proliferator-activated receptor β (PPARβ) attenuates cell proliferation and skin carcinogenesis, and this is due in part to regulation of ubiquitin C expression. In these studies, the role of PPARβ in modulating ubiquitin-dependent protein kinase Cα (PKCα) levels and phosphorylation signaling pathways was evaluated. Intracellular phosphorylation analysis showed that phosphorylated PKCα and other kinases were lower in wild-type mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) as compared with PPARβ-null mouse skin. No differences in expression levels of other PKC isoforms present in skin were observed. Lower ubiquitination of PKCα was found in TPA-treated PPARβ-null skin as compared with wild-type, and inhibition of ubiquitin-dependent proteasome degradation prevented TPA-induced down-regulation of PKCα. The activity of PKCα and downstream signaling kinases is enhanced, and expression of cyclooxygenase-2 (COX-2) is significantly greater, in PPARβ-null mouse skin in response to TPA compared with wild-type mouse skin. Inhibition of PKCα or COX-2 reduced cell proliferation in TPA-treated PPARβ-null keratinocytes in a dose-dependent manner, whereas it only slightly influenced cell proliferation in wild-type keratinocytes. Combined, these studies provide strong evidence that PPARβ attenuates cell proliferation by modulating PKCα/Raf1/MEK/ERK activity that may be due in part to reduced ubiquitin-dependent turnover of PKCα.

AB - Recent work has shown that peroxisome proliferator-activated receptor β (PPARβ) attenuates cell proliferation and skin carcinogenesis, and this is due in part to regulation of ubiquitin C expression. In these studies, the role of PPARβ in modulating ubiquitin-dependent protein kinase Cα (PKCα) levels and phosphorylation signaling pathways was evaluated. Intracellular phosphorylation analysis showed that phosphorylated PKCα and other kinases were lower in wild-type mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) as compared with PPARβ-null mouse skin. No differences in expression levels of other PKC isoforms present in skin were observed. Lower ubiquitination of PKCα was found in TPA-treated PPARβ-null skin as compared with wild-type, and inhibition of ubiquitin-dependent proteasome degradation prevented TPA-induced down-regulation of PKCα. The activity of PKCα and downstream signaling kinases is enhanced, and expression of cyclooxygenase-2 (COX-2) is significantly greater, in PPARβ-null mouse skin in response to TPA compared with wild-type mouse skin. Inhibition of PKCα or COX-2 reduced cell proliferation in TPA-treated PPARβ-null keratinocytes in a dose-dependent manner, whereas it only slightly influenced cell proliferation in wild-type keratinocytes. Combined, these studies provide strong evidence that PPARβ attenuates cell proliferation by modulating PKCα/Raf1/MEK/ERK activity that may be due in part to reduced ubiquitin-dependent turnover of PKCα.

UR - http://www.scopus.com/inward/record.url?scp=15744366162&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=15744366162&partnerID=8YFLogxK

U2 - 10.1074/jbc.M413808200

DO - 10.1074/jbc.M413808200

M3 - Article

C2 - 15632134

AN - SCOPUS:15744366162

VL - 280

SP - 9519

EP - 9527

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 10

ER -