Peroxisome proliferator-activated receptor-β/δ inhibits epidermal cell proliferation by down-regulation of kinase activity
Peroxisome proliferator-activated receptor-β/δ inhibits epidermal cell proliferation by down-regulation of kinase activity
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DOI：
10.1074/jbc.m413808200
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发表时间：
2005-03-11
影响因子：
4.8
通讯作者：
Peters, JM
中科院分区：
文献类型：
--
作者：
Kim, DJ;Murray, IA;Peters, JM
最近的研究表明，过氧化物酶体增殖物激活受体β（PPARbeta）减弱细胞增殖和皮肤癌的发生，这部分是由于泛素C表达的调节。在这些研究中，评估了PPARbeta在调节泛素依赖性蛋白激酶Calpha（PKCalpha）水平和磷酸化信号通路中的作用。细胞内磷酸化分析显示，与PPARbeta缺失小鼠皮肤相比，在用12-O-十四烷酰基佛波醇-13-乙酸酯（TPA）处理的野生型小鼠皮肤中磷酸化的PKCalpha和其它激酶较低。皮肤中其他PKC亚型的表达水平无差异。与野生型相比，在TPA处理的PPARbeta缺失皮肤中发现PKCalpha的泛素化较低，并且抑制泛素依赖性蛋白酶体降解防止TPA诱导的PKCalpha下调。与野生型小鼠皮肤相比，在响应TPA的PPARbeta-敲除小鼠皮肤中，PKCalpha和下游信号传导激酶的活性增强，并且环氧合酶-2（考克斯-2）的表达显著更高。抑制PKCalpha或考克斯-2以剂量依赖性方式减少TPA处理的PPARbeta缺失的角质形成细胞中的细胞增殖，而其仅轻微影响野生型角质形成细胞中的细胞增殖。结合，这些研究提供了强有力的证据表明，PPARbeta通过调节PKCalpha/Raf 1/MEK/ERK活性来减弱细胞增殖，这可能部分是由于PKCalpha的泛素依赖性周转减少。
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.