DMBA INDUCED SELF REGRESSING TUMORS--ROLE OF H-RAS

此续订申请解决了结果提出的问题 在本期内取得。它的重点是回归和 DMBA诱导的兔皮肤肿瘤呈现进展期。 在到目前为止获得的结果中，我们发现H-ras在 良性和自退性肿瘤(角化棘皮瘤，K.A.S) 明显低于鳞状细胞癌(SCC)。 这正发生在人类和兔子身上。突变的H-ras等位基因是 在KA的成熟期和退化期表达。我们现在就会 通过以下方法检验H-ras参与KA回归的假设 分析一系列体外和体内系统。我们将使用 稳定的兔角膜上皮细胞瞬时表达分析 在细胞培养中的表达和长期表型实验 转基因兔体内注射几种ras基因的构建 可诱导的角蛋白启动子的控制。 这将与转化生长因子β1、2和3的研究相结合。 在该系统中的表达，它们可能被ras癌基因和 它与该系统中的分化相关。 互补，并根据我们的初步结果，我们将研究其他 可能参与鳞状细胞癌进展过程的基因。到那时候 我们将完成一个显性癌基因的克隆 我们将分析其分子结构及其在皮肤中的作用 肿瘤进展.. 这一独特系统的分子特征既显示了 回归和级数应该对解剖 肿瘤发生过程及ras在其中的作用。

This renewal application addresses the questions raised by the results obtained in the present period. It focuses on the regression and progression phases that the DMBA induced skin tumors in rabbits present. In the results obtained so far we have found H-ras to be activated in benign and self-regressing tumors (keratoacanthomas, K.A.s) at a significantly lower frequency than in squamous cell carcinomas (SCCs). This is occurring in humans and rabbits. The mutant H-ras allele is expressed during the mature and regressing phases of the KA. We will now test the hypothesis that H-ras is involved in the KA regression by analyzing an array of in vitro and in vivo systems. We will use transient expression assays in rabbit corneal epithelial cells, stable expression in cell cultures and long term phenotypic experiments in transgenic rabbits injected with several ras constructions under the control of an inducible keratin promoter. This will be combined with the study of the TGF beta 1, 2, and 3 expression in this system, their possible induction by ras oncogenes and its correlation with differentiation in this system. Complementary, and based on our preliminary results, we will study other genes that could be involved in the process of progression to SCC. To that effect we will complete the cloning of a dominant oncogene detected in a rabbit SCC and we will analyze its molecular structure and role in skin tumors progression.. The molecular characterization of this unique system that displays both regression and progression should be very instrumental in dissecting the tumorigenesis process and the role of ras in it.