C-fos-dependent induction of the small ras-related GTPase Rab11a in skin carcinogenesis
C-fos-dependent induction of the small ras-related GTPase Rab11a in skin carcinogenesis
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DOI：
10.1016/s0002-9440(10)62969-0
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发表时间：
2005-07-01
影响因子：
6
通讯作者：
Hess, J
中科院分区：
文献类型：
--
作者：
Gebhardt, C;Breitenbach, U;Hess, J
由肿瘤促进剂和化学致癌物（例如佛醇酯12-O-十四酰基佛波醇-13-乙酸酯（TPA））引起的小鼠皮肤恶性转化是导致鳞状细胞癌形成的多阶段过程。已经显示缺乏AP-1家族成员c-Fos的小鼠表现出从良性到恶性皮肤肿瘤的受损转变。在这里，我们证明了增强表达的小Ras相关的GTdR Rab 11 a后，短期TPA治疗小鼠背部皮肤。Rab 11 a在体内和体外的表达严重依赖于c-Fos，因为TPA应用于c-Fos缺陷小鼠的背部皮肤和小鼠胚胎成纤维细胞不会诱导Rab 11 a mRNA或蛋白质表达。此外，地塞米松，这是一个有效的抑制剂AP-1介导的反式激活，表现出抗炎和抗肿瘤促进活动，抑制TPA诱导的Rab 11 a的表达。在Rab 11 a基因启动子中，我们发现了一个功能性AP-1结合元件，该元件在TPA处理角质形成细胞后表现出升高的c-Fos结合活性。增强的表达并不局限于化学诱导的小鼠皮肤肿瘤，但也发现在肿瘤标本来自上皮皮肤肿瘤患者。这些数据将Rab 11 a确定为一种新的肿瘤相关c-Fos/AP-1靶点，并可能指出Rab 11 a在皮肤癌发展中尚未被认识到的功能。
Malignant transformation of mouse skin by tumor promoters and chemical carcinogens, such as the phorhol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), is a multistage process leading to the formation of squamous cell carcinomas. it has been shown that mice lacking the AP-1 family member c-Fos exhibit an impaired transition from benign to malignant skin tumors. Here, we demonstrate enhanced expression of the small Ras-related GTPase Rab11a after short-term TPA treatment of mouse back skin. Expression of Rab11a in vivo and in vitro critically depended on c-Fos, because TPA application to the back skin of c-Fos-deficient mice and to mouse embryonic fibroblasts did not induce Rab11a mRNA or protein expression. Moreover, dexamethasone, which is a potent inhibitor of AP-1-mediated transactivation that exhibits anti-inflammatory and antitumor promoting activities, inhibited TPA-induced expression of Rab11a. Within the Rab11a gene promoter, we identified a functional AP-1 binding element that exhibited elevated c-Fos binding activity after TPA treatment of keratinocytes. Enhanced expression was not restricted to chemically induced mouse skin tumors but was also found in tumor specimens derived from patients with epithelial skin tumors. These data identify Rab11a as a novel, tumor-associated c-Fos/AP-1 target and may point to an as yet unrecognized function of Rab11a in the development of skin cancer.