Dr. Guillermina Lozano
The University of Texas MD Anderson Cancer Center
Department of Genetics
Mutation of the p53 tumor suppressor is a critical event in the elaboration of many tumors of diverse origin. Other alterations in components of the p53 pathway, such as amplification or overexpression of Mdm2 and Mdm4, which encode potent p53 inhibitors, also contribute to tumorigenesis. The overall goal of my laboratory is to understand the signals that regulate the p53 pathway and the consequences of expressing mutant p53 in vivo.
Toward these goals, we have generated more than twenty alleles in mice that disrupt the p53 pathway. Mice expressing the p53R172H mutation develop osteosarcomas and carcinomas that metastasized at very high frequency. We are currently exploring the mechanisms of how mutant p53 contributes to metastasis. The p53R172P mutant transactivates genes involved in cell cycle arrest but not apoptosis and mice exhibit delayed tumorigenesis indicating that p53 activities other than apoptosis are also critical for tumor suppression. Other p53 alleles allow us to restore p53 function in various tumors and monitor effects on tumor progression. Currently, we are studying a somatic model of p53 in which the p53 mutation occurs in a single cell surrounded by normal stroma. Other mouse models probe the importance of components of the p53 pathway. For example, loss of Mdm2 or Mdm4 results in embryonic lethality that is completely rescued by concomitant loss of p53, and a single nucleotide polymorphism in Mdm2 is associated with increased risk of cancer in humans and mice. These studies indicate the importance of regulating p53 activity in development and tumorigenesis.