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. ? ? ?
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| Vilgelm, Anna E; Washington, Mary K; Wei, Jinxiong et al. (2010) Interactions of the p53 protein family in cellular stress response in gastrointestinal tumors. Mol Cancer Ther 9:693-705 |
| Vilgelm, Anna; El-Rifai, Wael; Zaika, Alexander (2008) Therapeutic prospects for p73 and p63: rising from the shadow of p53. Drug Resist Updat 11:152-63 |
| Wei, Jinxiong; O'Brien, Daniel; Vilgelm, Anna et al. (2008) Interaction of Helicobacter pylori with gastric epithelial cells is mediated by the p53 protein family. Gastroenterology 134:1412-23 |
