NEOPLASTIC TRANSFORMATION OF HUMAN EPITHELIAL CELLS BY ONCOGENES

ras、raf、jun、erbB-2（neu）五个活化原癌基因家族 和myc与人支气管癌有关。 体外培养的人支气管上皮细胞正被用于研究 这些特定癌基因的功能作用和生长调节 致癌和肿瘤进展的基因。 erbB-2过表达 导致人支气管上皮细胞的肿瘤转化。 ras和raf myc基因诱导肿瘤细胞增殖的分子机制 转型是当前和未来研究的主要焦点。 我们 研究ras和raf在细胞信号转导中的作用， 配体激活细胞膜受体到细胞核， 随后改变生长和终末分化的表达 基因. 我们假设受体介导的raf磷酸化 激酶导致其活性增加和转运到 原子核 活化的raf激酶的可能底物包括PI 激酶和核调节蛋白，myc和p53。 的影响 突变型p53基因对细胞生长和终末鳞状分化的影响 进行评估。 突变型p53和ras基因在胃癌中的协同作用 人正常支气管的“永生化”与肿瘤转化 正在研究上皮细胞。 人乳头瘤病毒16和18具有 已被证明可以使正常的支气管上皮细胞“永生化”。 以来 Ha-ras或myc/raf转化的支气管上皮细胞高度表达 在无胸腺裸鼠中的侵袭性和转移性，我们计划研究 被认为与肿瘤有关的基因的调节和表达 转移包括Nm 23、胶原酶IV和TIMP-2。

Five families of activated protooncogenes, ras, raf, jun, erbB-2 (neu) and myc have so far been associated with human bronchogenic carcinoma. Human bronchial epithelial cells in vitro are being used to investigate the functional role of these specific oncogenes and growth regulatory genes in carcinogenesis and tumor progression. Overexpression of erbB-2 causes neoplastic transformation of human bronchial epithelial cells. The molecular mechanisms of ras and raf myc induction of neoplastic transformation is the major focus of current and future studies. We are investigating the role of ras and raf in the transduction of signals from ligand activated cellular membrane receptors to the nucleus and subsequent altered expression of growth and terminal differentiation genes. We hypothesize that receptor-mediated phosphorylation of the raf kinase causes both an increase in its activity and a translocation to the nucleus. Possible substrates of the activated raf kinase include PI kinase and nuclear regulatory proteins, myc and p53. The effects of mutant p53 gene on cell growth and terminal squamous differentiation will be assessed. The cooperativity of mutant p53 and ras genes in the "immortalization" and neoplastic transformation of normal human bronchial epithelial cells is being studied. Human papillomaviruses 16 and 18 have been shown to "immortalize" normal bronchial epithelial cells. Since the Ha-ras or myc/raf transformed bronchial epithelial cells are highly invasive and metastatic in athymic nude mice, we plan to investigate the regulation and expression of genes considered to be involved in tumor metastasis including Nm23, collagenase IV and TIMP-2.