Molecular basis of squamous differentiation and neoplasia in skin & oral tiss

E绝大多数癌症发生在口腔 空洞是鳞状细胞癌。角质形成细胞生物学 该小组成立于1998年1月，目的是阐明 鳞状细胞分化与生化改变 有助于肿瘤表型和恶变。 我们的工作利用了小鼠表皮的角质形成细胞和 在体外和体内的方法来解剖的阶段 分化与肿瘤进展。P53肿瘤 在大多数人类中，抑制基因发生突变或失活 癌症，包括口腔癌症，以及我们的研究 集中于阐明其作用的功能和机制 这种基因产物在角质形成细胞生物学中的应用。骑自行车 依赖性激酶抑制因子WAF1，P53的下游靶点 介导的基因转录，被认为是一种效应因子 P53对肿瘤的抑制作用。我们探讨了WAF1的作用 基因产物在多步致癌中的应用 体内和体外模型已经证明WAF1的丢失是 不足以解释P53缺失的恶性表型 肿瘤；因此，除了转录激活外，P53的其他特征 WAF1基因是其抑癌基因所必需的 功能。此外，通过差异显示分析，我们有 发现了一个新的p53调控基因，它也是 肿瘤坏死因子-α途径并发现这种过度表达 基因产物可迅速诱导角质形成细胞死亡。 因为在大多数癌症中，P53蛋白是失活的 发生在口腔中，阐明这一途径应该有助于 阐明口腔癌变的病因并提出新的建议 治疗性干预。“

e vast majority of cancers arising in the oral cavity are squamous cell carcinomas. The Keratinocyte Biology Group was established in January, 1998 to elucidate mechanisms of squamous cell differentiation and the biochemical alterations contributing to the neoplastic phenotype and malignant conversion. Our work has utilized keratinocytes of murine epidermis and both in vitro and in vivo approaches to dissect the stages of differentiation and neoplastic progression. The p53 tumor suppressor gene is mutated or inactivated in a majority of human cancers, including those of the oral cavity, and our studies have focused on elucidating the function and mechanism of action of this gene product in keratinocyte biology. The cyclin dependent kinase inhibitor WAF1, a downstream target of p53 mediated gene transcription, is believed to be an effector of tumor suppression by p53. We have explored the role of the WAF1 gene product in multistep carcinogenesis, and using both in vivo and in vitro models have demonstrated that loss of WAF1 is not sufficient to explain the malignant phenotype of p53 null tumors; thus, other features of p53 beside transcriptional activation of the WAF1 gene are necessary for its tumor suppressor function. In addition, by differential display analysis we have identified a novel p53 regulated gene that is also part of the TNF-alpha pathway and have found that this overexpression of this gene product rapidly induces keratinocyte cell death. Because the p53 protein is inactivated in a majority of cancers arising in the oral cavity, elucidating this pathway should help to clarify the etiology of oral carcinogenesis and suggest novel therapeutic interventions."