Risk Factors for Cell Transformation and the Role of Apoptosis

正常的机体内稳态是通过细胞增殖和细胞死亡过程的小心平衡来维持的。癌细胞在快速分裂和扩张的同时，也可能发生细胞死亡。了解癌细胞如何死亡或失去对细胞死亡过程的易感性是很重要的。我们已经表明，在肿瘤过程的不同阶段，细胞对凋亡的易感性是不同的。在单独的研究中，我们正在研究细胞凋亡途径对氧化损伤的反应。在研究p53在这一过程中的作用后，我们发现细胞凋亡似乎也需要p85激酶。此外，我们还发现Rb蛋白可能是细胞在受伤后决定是停止还是自杀的关键因素。此外，我们也一直在研究EIA结合p300蛋白作为多种细胞反应的整合者的作用。我们发现p300可以在细胞应激条件下与c-fos蛋白偶联，从而导致细胞凋亡。c-fos的升高已被证明是低血清诱导的仓鼠成纤维细胞凋亡的关键事件。我们认为c-fos与p300的结合对于细胞决定是否发生细胞死亡至关重要。此外，我们正在开始研究早期基因对各种诱导氧自由基的药物的反应。我们希望利用cDNA微阵列技术建立细胞对这类药物反应的分子特征。最后，我们研究了IGFI在保护前列腺癌细胞免于凋亡中的作用，以及饮食限制在抑制TRAMP转基因小鼠前列腺肿瘤中的作用。今年是这个项目的最后一年。任何进一步的研究将在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.