INHIBITION OF CELL PROLIFERATION BY ETHANOL

描述(改编自《调查者摘要》)：习惯 即使是适量的酒精饮料(一至两杯) 每天饮酒)会导致大量的临床、生化和 酒精对人体的毒性作用所产生的生理发现 肝脏、骨髓、脑和骨骼等。一种病理效应 乙醇对细胞增殖的影响在所有这些靶点中都有描述。 纸巾。然而，对酒精诱导的生长抑制的调查 到目前为止，细胞水平还没有发现这一现象的机制 不利的影响。PI的实验室已经证实了它的抑制作用 临床相关浓度乙醇对体外培养细胞增殖的影响 在一个定义明确的成骨细胞模型系统中。对这一效应的进一步研究 研究表明，乙醇诱导的生长抑制与以下因素平行 抑制丝裂原活化蛋白(MAP)激酶活性。地图 激酶蛋白磷酸化级联反应在触发信号转导中起重要作用 细胞增殖和MAPK的激活是通过连续的 刺激RAS激活途径中的特定蛋白(RAS，Raf-1， 和MAP激酶)。但乙醇对MAP激酶无抑制作用 过度表达具有结构性活性的RAS基因的细胞中的活性。这些 观察表明，乙醇干扰了细胞内的一个重要部位。 靠近RAS作用的增殖途径。RAS激活 是受体酪氨酸激酶诱导有丝分裂所必需的， 最近，适配分子和GTP交换蛋白参与了 RAS已经被实验性地描述过。基于这些耐人寻味 据观察，假设乙醇能抑制细胞 通过干扰酪氨酸激酶中的特定位点实现增殖 导致RAS激活的磷酸化途径。具体的 该方案的目标是：(1)表征细胞内的 生长因子依赖的RAS激活所需的信号通路 乙醇干扰的成骨细胞(S)；(2)确定部位(S) 在生长因子受体酪氨酸激酶通路中的作用 乙醇；(3)确定乙醇的分子机制(S) 干扰生长因子酪氨酸激酶信号转导通路 成骨细胞。乙醇能抑制多种组织的生长，而且 IGF轴无处不在，调节所有类型细胞的生长发育。 我们在这个模型骨细胞系统中的观察可能会提供新的 对乙醇抗增殖作用的总体洞察。

DESCRIPTION (Adapted from the Investigator's Abstract): The habitual consumption of even moderate quantities of alcoholic beverages (one to two drinks per day) can result in a host of abnormal clinical, biochemical, and physiologic findings that stem from the toxic effects of alcohol on the liver, marrow, brain and skeleton among others. A pathological effect of ethanol on cellular proliferation has been described in all of these target tissues. Yet, the investigation of alcohol-induced growth suppression at the cellular level has, thus far, failed to uncover the mechanism of this adverse effect. The PI's laboratory has confirmed the inhibitory effect of clinically relevant concentrations of ethanol on cell proliferation in vitro in a well-defined osteoblast model system. Additional study of this effect revealed that the growth suppression induced by ethanol was paralleled by suppression of mitogen-activated protein (MAP) kinase activity. The MAP kinase protein phosphorylation cascade plays an essential role in triggering cell proliferation and activation of MAP kinase occurs through successive stimulation of specific proteins in the Ras activation pathway (Ras, Raf-1, and MAP kinase). However, ethanol exerts no inhibitory effect on MAP kinase activity in cells overexpressing a constitutively active Ras gene. These observations indicate that ethanol interferes with an important site in the proliferation pathway that is proximal to the action of Ras. Ras activation is necessary for mitogenesis induced by the receptor tyrosine kinases and, recently, the involvement of adapter molecules and GTP exchange proteins for Ras has been experimentally described. Based on these intriguing observations, it is hypothesized that ethanol inhibits cellular proliferation by interfering with a specific site in the tyrosine kinase phosphorylation pathway that leads to the activation of Ras. The specific objectives of this proposal are : (1) to characterize the intracellular signaling pathway necessary for growth factor-dependent activation of Ras in the osteoblast(s) that is perturbed by ethanol; (2) to identify the site(s) of in the growth factor receptor tyrosine kinase pathway affected by ethanol; (3) to determine the molecular mechanism(s) by which ethanol interferes with growth factor tyrosine kinase signaling pathway in the osteoblast. Ethanol inhibits growth in a wide variety of tissues and the IGF axis is ubiquitous, regulating growth and development of all cell types. Our observations in this model bone cell system are likely to provide fresh insights into the anti-proliferative actions of ethanol in general.