Role of β-TrCP ubiquitin ligase receptor in UVB mediated responses in skin.
Role of β-TrCP ubiquitin ligase receptor in UVB mediated responses in skin.
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DOI：
10.1016/j.abb.2010.12.023
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发表时间：
2011-04-15
影响因子：
3.9
通讯作者：
Spiegelman VS
中科院分区：
文献类型：
--
作者：
Bhatia N;Demmer TA;Sharma AK;Elcheva I;Spiegelman VS
皮肤癌是美国最常见的癌症。暴露于UVB辐射是诱发皮肤癌的主要危险因素。SCFβ-TrCP E3泛素连接酶参与细胞周期、细胞增殖和细胞转化。在癌细胞系和原发性肿瘤中经常发现含有β-转导素重复序列的蛋白（β-TrCP）的异常上调。我们先前已经证明，β-TrCP 2在化学诱导的小鼠皮肤肿瘤中过表达。各种细胞应激刺激，包括UVB，诱导人细胞中β-TrCP 1 mRNA和蛋白水平的增加。我们先前已经表明，在体外hTERT永生化的正常角质形成细胞中，通过诱导显性负性β-TrCP 2（β-TrCP 2 ΔF）来抑制β-TrCP功能，导致UVB诱导的细胞凋亡增加。我们用角蛋白5启动子（K5-rTA × TRE-HA-β-TrCPΔF）产生了表皮中显性负性β-TrCP 2可诱导、选择性表达的转基因小鼠。在这里，我们报告，β-TrCP功能的抑制在小鼠表皮中导致UVB诱导的皮肤水肿，增生和炎症反应的减少和UVB诱导的细胞凋亡的增加。我们的研究结果表明，β-TrCP可能是UVB诱导的皮肤反应的重要参与者，并可能成为皮肤癌的潜在治疗靶点。
Skin cancers are the most common cancers in the United States. Exposure to UVB radiation is a major risk factor for skin cancer induction. SCFβ-TrCP E3 ubiquitin ligase has been found to be involved in cell cycle, cell proliferation and transformation. Aberrant up-regulation of beta-transducin repeats-containing proteins (β-TrCP) is often found in cancer cell lines and primary tumors. We have previously demonstrated that β-TrCP2 is over-expressed in chemically induced mouse skin tumors. Various cellular stress stimuli, including UVB, induce an increase in β-TrCP1 mRNA and protein levels in human cells. We have previously shown that inhibition of β-TrCP function, by induction of dominant negative β-TrCP2 (β-TrCP2ΔF), in vitro in hTERT immortalized normal keratinocytes, results in increase in UVB induced apoptosis. We have generated transgenic mice with inducible, selective expression of dominant negative β-TrCP2 in epidermis with the Keratin 5 promoter (K5-rTA × TRE-HA-β-TrCPΔF). Here we report that inhibition of β-TrCP function in mouse epidermis results in decrease in UVB-induced edema, hyperplasia, and inflammatory response and increment in UVB-induced apoptosis in skin. Our results suggest that β-TrCP may be an essential player in UVB induced responses in skin and can be a potential therapeutic target for skin cancer.