Risk Factors for Cell Transformation and the Role of Apoptosis

正常的机体内环境平衡是通过仔细平衡细胞增殖和细胞死亡过程来维持的。癌细胞在快速分裂和扩张的同时，也可能经历细胞死亡。了解癌细胞如何死亡或失去对细胞死亡过程的敏感性是很重要的。我们已经证明，在肿瘤过程的不同阶段，细胞对凋亡的敏感性是不同的。在单独的研究中，我们正在探索氧化损伤反应中的细胞凋亡途径。在跟踪P53在这一过程中的作用的研究中，我们发现细胞凋亡似乎也需要P85激酶。此外，我们还发现，Rb蛋白可能在细胞决定是否在受伤后逮捕或自杀中起关键作用。此外，我们还一直在研究EIA结合的p300蛋白作为多种细胞反应的整合因子的作用。我们已经发现，在导致细胞凋亡的应激条件下，p300可以与c-fos蛋白偶联。C-fos的升高是低血清诱导金黄地鼠成纤维细胞凋亡的关键事件。我们认为，c-fos与p300的结合是细胞决定细胞死亡的关键。此外，我们正在开始研究各种诱导氧自由基的试剂对早期基因的反应。我们希望利用基因芯片技术来建立细胞对这类药物反应的分子标记。最后，我们正在研究IGFI在保护前列腺癌细胞免受凋亡中的作用，以及限制饮食在限制前列腺癌方面的作用。这是这个项目的最后一年。任何进一步的研究都将在NCI进行。

Normal organismal homeostasis is maintained through a careful balance of cell proliferation and cell death processes. Cancer cells, while rapidly undergoing division and expansion, may also undergo cell death. It is important to understand how cancer cells die or lose their susceptibility to the cell death process. We have shown that the susceptibility of cells at various stages of the neoplastic process to undergo apoptosis differs. In separate studies, we are pursuing the apoptotic pathway in response to oxidative damage. In studies following the role of p53 in this process, we have found that apoptosis also appears to require the p85 kinase. In addition we have found that the Rb protein may be a key player in the cellular decision whether to arrest or commit suicide following injury. In addition, we have also been examining the role of the EIA binding, p300 protein, as an integrator of multiple cellular responses. We have found that p300 can couple with the c-fos protein under conditions of cellular stress that result in apoptosis. The elevation of c-fos has been shown to be a key event in low serum induced apoptosis of hamster fibroblasts. We propose that the binding of c-fos to p300 is critical for the cellular decision to undergo cell death. In addition, we are beginning studies to examine the early gene response to a variety of agents that induce oxygen free radicals. We hope to use cDNA microarray technology to establish a molecular signature of the cellular response to this class of agents. Finally, we are examining the role of IGFI in protecting prostate cancer cells from apoptosis and the effect of dietary restriction in TRAMP transgenic mice in limiting prostate neoplasms. This is the final year for this project. Any further research will be done at NCI.