Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 280, Issue 10, Pages 9519-9527Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M413808200
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Funding
- NCI NIH HHS [CA89607, CA97999] Funding Source: Medline
- NIEHS NIH HHS [ES04869] Funding Source: Medline
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Recent work has shown that peroxisome proliferator-activated receptor beta(PPARbeta) attenuates cell proliferation and skin carcinogenesis, and this is due in part to regulation of ubiquitin C expression. In these studies, the role of PPARbeta in modulating ubiquitin-dependent protein kinase Calpha (PKCalpha) levels and phosphorylation signaling pathways was evaluated. Intracellular phosphorylation analysis showed that phosphorylated PKCalpha and other kinases were lower in wild-type mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) as compared with PPARbeta-null mouse skin. No differences in expression levels of other PKC isoforms present in skin were observed. Lower ubiquitination of PKCalpha was found in TPA-treated PPARbeta-null skin as compared with wild-type, and inhibition of ubiquitin-dependent proteasome degradation prevented TPA-induced down-regulation of PKCalpha. The activity of PKCalpha and downstream signaling kinases is enhanced, and expression of cyclooxygenase-2 (COX-2) is significantly greater, in PPARbeta-null mouse skin in response to TPA compared with wild-type mouse skin. Inhibition of PKCalpha or COX-2 reduced cell proliferation in TPA-treated PPARbeta-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 PPAR beta attenuates cell proliferation by modulating PKCalpha/Raf1/MEK/ERK activity that may be due in part to reduced ubiquitin-dependent turnover of PKCalpha.
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