Integral activity of the p53 family and its role in progression of colon tumors

描述（由申请人提供）：结直肠癌（CRC）仍然是美国最常诊断的胃肠道癌症，也是癌症死亡的第二大常见原因。大约一半的结直肠肿瘤携带p53基因突变。对p53肿瘤抑制因子的广泛研究已经证明了这种分子在预防结直肠肿瘤发生中的关键作用。然而，全面的临床分析发现，p53突变的预后价值，虽然有希望，仍然没有达到临床有用的水平，因为目前的方法评估p53异常是不可靠的。事实上，越来越多的数据表明，p53蛋白家族的其他成员，p73和p63，强烈影响p53活性，但他们没有占突变分析。p63和p73的上调与许多人类肿瘤的不良临床病理结果相关。同时，这些蛋白质在功能上与p53相互作用，并对细胞凋亡和细胞周期控制有深远的影响，正如我们的初步研究所证明的那样。总之，这些数据表明p53家族内部的相互作用可能参与CRC的发生和进展。我们建议描绘整个p53蛋白家族的转录活性在结肠肿瘤中的作用。我们开发了一种新的慢病毒方法，使我们能够测量原代人类肿瘤细胞中整个p53肿瘤抑制通路的功能活性。这为我们首次评估p53家族在细胞凋亡中的整体作用并更精确地评估其在肿瘤进展中的作用提供了独特的机会。此外，使用一些细胞和分子生物学技术，我们将表征p53家族成员之间的功能相互作用的作用。这些信息可能为开发新的预后和治疗靶点提供新的途径。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) remains the most commonly diagnosed gastrointestinal cancer and the second most common cause of cancer death in the United States. Approximately half of all colorectal tumors carry mutations in p53 gene. Extensive studies of the p53 tumor suppressor have demonstrated a pivotal role of this molecule in preventing colorectal tumorigenesis. However, comprehensive clinical analysis has found that the prognostic value of p53 mutations, though promising, still does not reach the level of clinical usefulness because current methods of assessing p53 abnormalities are not reliable. In fact, accumulating data suggest that other members of the p53 protein family, p73 and p63, strongly affect the p53 activity but they are not accounted for by mutational analysis. The upregulation of p63 and p73 correlates with poor clinicopathological outcome in a number of human tumors. At same time, these proteins functionally interact with p53 and have profound effects on apoptosis and cell cycle control, as has been demonstrated in our preliminary studies. Taken altogether, these data suggest that interactions inside the p53 family can be involved in development and progression of CRC. We propose to delineate the role of transcriptional activity of the entire p53 protein family in colon tumors. We have developed a novel lentiviral approach, which allows us to measure the functional activity of the entire p53 tumor suppressor pathway in primary human tumor cells. This gives us a unique opportunity for the first time to evaluate the integral role of the p53 family in apoptosis and more precisely assess its role in tumor progression. In addition, using a number of cellular and molecular biology techniques, we will characterize the role of functional interactions between members of the p53 family. This information may provide new avenues for the development of novel prognostic and therapeutic targets.