Protein kinase Cε, which sensitizes skin to sun's UV radiation-induced cutaneous damage and development of squamous cell carcinomas, associates with Stat3
Protein kinase Cε, which sensitizes skin to sun's UV radiation-induced cutaneous damage and development of squamous cell carcinomas, associates with Stat3
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DOI：
10.1158/0008-5472.can-06-3350
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发表时间：
2007-02-01
期刊：
影响因子：
11.2
通讯作者：
Verma, Ajit K.
中科院分区：
文献类型：
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作者：
Aziz, Moammir H.;Manoharan, Herbert T.;Verma, Ajit K.
慢性暴露于紫外线辐射（UVR）是人类皮肤癌（包括鳞状细胞癌[SCC]）发生的主要病因因素。我们已经表明，蛋白激酶C ε（PKC ε），一种不依赖Ca²⁺、依赖磷脂的丝氨酸/苏氨酸激酶，是一种内源性光敏剂。PKC ε是在小鼠和人类皮肤中均表达的六种同工型（α、δ、ε、η、μ和ζ）之一。在基底表皮细胞和毛囊细胞中过表达PKC ε的PKC ε转基因小鼠对紫外线辐射诱导的皮肤损伤和鳞状细胞癌的发生高度敏感。我们现在发现，过表达PKC ε而非过表达PKC δ的转基因小鼠，在暴露于由柯达赛尔滤光片过滤的FS - 40太阳灯发出的单次（4 kJ/m²）或重复（四次剂量，2 kJ/m²/次，每周三次）紫外线辐射时，会引起信号转导子和转录激活子3（Stat3）在Tyr705和Ser727残基的组成性磷酸化。紫外线辐射诱导的Stat3磷酸化伴随着Stat3调控基因（c - myc、细胞周期蛋白D1、cdc25A和COX - 2）表达增加。在相互免疫沉淀/印迹实验中，磷酸化的Stat3与PKC ε共免疫沉淀。正如在体内使用PKC ε基因敲除小鼠以及在体外免疫复合物激酶测定中所观察到的，PKC ε使Stat3在Ser727残基磷酸化。这些结果首次表明：（a）PKC ε是一种Stat3 Ser727激酶；（b）PKC ε介导的Stat3 Ser727磷酸化可能对Stat3的转录活性至关重要；（c）紫外线辐射诱导的Ser727磷酸化可能是PKC ε赋予对紫外线辐射诱导的鳞状细胞癌发生敏感性的机制的一个关键组成部分。
Chronic exposure to UV radiation (UVR) is the major etiologic factor in the development of human skin cancers including squamous cell carcinoma (SCC). We have shown that protein kinase C epsilon (PKC epsilon), a Ca2+-independent, phospholipid-dependent serine/threonine kinase, is an endogenous photosensitizer. PKC epsilon is among the six isoforms (alpha, delta, epsilon, eta, mu, and zeta) expressed in both mouse and human skin. PKC epsilon transgenic mice, which overexpress PKC epsilon in the basal epidermal cells and cells of the hair follicle, are highly sensitive to UVR-induced cutaneous damage and development of SCC. We now present that PKC epsilon-overexpressing, but not PKC delta-overexpressing, transgenic mice, when exposed to a single (4 kJ/m(2)) or repeated (four doses, 2 kJ/m(2)/dose, thrice weekly) UVR, emitted by Kodacel-filtered FS-40 sun lamps, elicit constitutive phosphorylation of signal transducers and activators of transcriptions 3 (Stat3) at both Tyr705 and Ser727 residues. UVR-induced phosphorylation of Stat3 accompanied increased expression of Stat3-regulated genes (c-myc, cyclin D1, cdc25A, and COX-2). In reciprocal immunoprecipitation/blotting experiments, phosphorylated Stat3 coimmunoprecipitated with PKC epsilon. As observed in, vivo using PKC epsilon knockout mice and in vitro in an immunocomplex kinase assay, PKC epsilon phosphorylated Stat3 at Ser727 residue. These results indicate for the first time that (a) PKC epsilon is a Stat3Ser727 kinase; (b) PKC epsilon-mediated phosphorylation of StatSer727 may be essential for transcriptional activity of Stat3; and (c) UVR-induced phosphorylation of Ser727 may be a key component of the mechanism by which PKCe imparts sensitivity to UVR-induced development of SCC.