ROLE OF GKLF IN EPITHELIAL DYSPLASIA

描述：(改编自研究者的摘要)隐性遗传 肿瘤抑制基因的改变经常激活野生型 在下游发挥作用的转化癌基因的类型等位基因 生化途径。在正常上皮中，但在高度发育异常的上皮中不存在 在上皮中，这些癌基因的表达仅限于特定的间隔室。 GKLF是癌症中一种主要的转化活性，通常在肿瘤中表达 在复层鳞状上皮的分化细胞层中。在……里面 发育不良的上皮细胞，表达显著增加，并在ALL中存在 细胞层，这表明基础细胞层的抑制可能会消失 在肿瘤进展的早期。GKLF表达持续上调 在口腔鳞状细胞癌的进展过程中，并通过在口腔鳞状细胞癌的 在三分之二的乳腺癌中进行原位杂交。GKLF的强制表达 在转基因小鼠的基底细胞层中，皮肤诱导上皮细胞的特征 发育不良，包括根尖-基底极化丧失和角化过度。在……里面 RK3E上皮细胞，GKLF特异性抑制整合素的表达 基底膜成分胶原和层粘连蛋白的受体。表达式 玻璃连接蛋白/纤维连接蛋白受体组分的AV不受GKLF的抑制。 与这些结果一致的是，GKLF转化的细胞表现出明显的 降低了与胶原或层粘连蛋白的附着率，但保留了或 增加对细胞外基质成分Vitronectin和Vitronectin的附着 纤维连接蛋白。这些结果确定GKLF是一个候选决定因素 通过整合素功能调节的发育异常表型。通过激活 GKLF的表达，肿瘤细胞可能获得正常的性质 分化上皮细胞，释放基底膜的能力 并附着在细胞外基质的其他成分上。在…的第一个目标中 在这项提议中，鲁珀特博士将GKLF转基因小鼠的皮肤表征为 在人类肿瘤损伤中发现的分子改变，包括丢失 整合素表达。在第二个目标中，他还将测试老鼠的 容易形成肿瘤，并使用诱导系统测试 下调GKLF在发育不良上皮和肿瘤中的作用。在 第三个目标，他将使用RK3E细胞来进一步表征 GKLF对整合素表达的调节，并测定其频率和 乳腺癌和口腔肿瘤中GKLF激活的时机。

DESCRIPTION: (Adapted from the investigator's abstract) Recessive genetic alterations in tumor suppressor genes frequently activate expression of wild type alleles of transforming oncogenes that function downstream in a biochemical pathway. In normal epithelium, but not in highly dysplastic epithelium, expression of these oncogenes is limited to specific compartments. GKLF is a major transforming activity in carcinomas that is normally expressed in the differentiating cell layers of stratified squamous epithelium. In dysplastic epithelium, expression is greatly increased and is present in all cell layers, suggesting that suppression in the basal cell layer may be lost early during tumor progression. GKLF expression is consistently upregulated during progression of oral squamous cell carcinoma, and is detected by mRNA in situ hybridization in two-thirds of breast cancers. Enforced expression of GKLF in the basal cell layer of transgenic mouse skin induces features of epithelium dysplasia, including loss of apical-basal polarization and hyperkeratosis. In RK3E epithelial cells, GKLF specifically inhibits expression of integrin receptors for the basement membrane components collagen and laminin. Expression of the vitronectin/fibronectin receptor component aV was not inhibited by GKLF. Consistent with these results, GKLF-transformed cells exhibited a markedly reduced rate of attachment to the collagen or laminin, but retained or increased attachment to the extracellular matrix components vitronectin and fibronectin. These results identify GKLF as a candidate determinant of the dysplastic phenotype through regulation of integrin function. By activating expression of GKLF, tumor cells may acquire a property of normal differentiating epithelial cells, the ability to release the basement membrane and attach to other components of the extracellular matrix. In the first aim of this proposal, Dr. Ruppert will characterize GKLF transgenic mouse skin for molecular alterations found in human neoplastic lesions, including loss of integrin expression. In the second aim, he will also test mice for predisposition to tumor formation, and use an inducible system to test the effects of downregulating GKLF in dysplastic epithelium and tumors. In the third aim he will use RK3E cells to further characterize the mechanism of regulation of integrin expression by GKLF, and to determine the frequency and timing of GKLF activation in breast cancers and oral tumors.