Xu Yiru, Voorhees John J, Fisher Gary J
Department of Dermatology, University of Michigan Medical School, Medical Science I, Room 6447, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0609, USA.
Am J Pathol. 2006 Sep;169(3):823-30. doi: 10.2353/ajpath.2006.050449.
Epidermal growth factor receptor (EGFR) is a critical mediator of several types of epithelial cancers. Skin cancer arising from exposure to ultraviolet B irradiation (UVB) from the sun is a prominent form of human cancer. Recent data indicate that in addition to cognate ligands, EGFR is activated by UVB irradiation. We used pharmacological and genetic approaches to investigate the function of EGFR in mediating UVB-induced signal transduction in human skin keratinocyte HaCaT cells. Pharmacological inhibition of EGFR tyrosine kinase significantly inhibited UVB-mediated induction of ERK, p38, and JNK MAP kinases, and their effectors, transcription factors c-Fos and c-Jun. Inhibition of UVB activation of EGFR also suppressed activation of AKT-, PKC-, and PKA-dependent signal transduction pathways. B82 mouse L cells devoid of EGFR were used to further investigate EGFR dependence of UVB-induced signal transduction. UVB failed to induce ERK, and JNK activation was reduced 60% in B82 cells compared to B82K+ cells, which express EGFR. In addition, UVB induced both c-Fos and c-Jun proteins in B82K+ cells, whereas neither were induced in B82 cells. Taken together, these data demonstrate that EGFR is required for UVB-mediated induction of multiple signaling pathways that are known to mediate tumor formation in skin.
表皮生长因子受体（EGFR）是多种上皮癌的关键介质。因暴露于太阳紫外线B辐射（UVB）而引发的皮肤癌是人类癌症的一种主要形式。最近的数据表明，除了同源配体之外，EGFR还可被UVB辐射激活。我们采用药理学和遗传学方法来研究EGFR在介导人皮肤角质形成细胞HaCaT细胞中UVB诱导的信号转导中的功能。对EGFR酪氨酸激酶的药理学抑制显著抑制了UVB介导的ERK、p38和JNK丝裂原活化蛋白激酶及其效应分子转录因子c-Fos和c-Jun的诱导。对EGFR的UVB激活的抑制也抑制了AKT、PKC和PKA依赖性信号转导途径的激活。利用缺乏EGFR的B82小鼠L细胞进一步研究UVB诱导的信号转导对EGFR的依赖性。与表达EGFR的B82K+细胞相比，UVB未能在B82细胞中诱导ERK，且JNK激活降低了60%。此外，UVB在B82K+细胞中诱导了c-Fos和c-Jun蛋白，而在B82细胞中均未诱导。综上所述，这些数据表明EGFR是UVB介导的多种已知介导皮肤肿瘤形成的信号通路诱导所必需的。
