Dr. Guillermina Lozano
The University of Texas MD Anderson Cancer Center
Department of Genetics
Mutation of the p53 gene is a critical event in the elaboration of many tumors of diverse origin. The p53 protein is activated in response to DNA damage, serving as a checkpoint in the elimination or repair of cells with damaged DNA. Alterations in components of the p53 pathway, such as amplification of the mdm2 gene, which encodes a p53 inhibitor, 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 wild-type or mutant p53.
Toward this goal, we are generating mouse models to address the importance of various p53 mutations in tumor development in vivo. The first mice generated were those expressing a common p53 mutation identified in human cancers. Mice expressing the p53R172H mutant develop osteosarcomas and carcinomas that metastasized at very high frequency. This study also indicates that mutant p53 is inherently unstable in vivo suggesting that other genetic alterations in tumor cells stabilize p53. We have generated mice with another interesting mutant that distinguishes the ability of p53 to induce apoptosis or cell cycle arrest. The p53R172P mutant cannot transactivate genes that induce apoptosis yet retains the ability to induce the p21 gene involved in cell cycle arrest. Importantly, this mutant shows delayed tumorigenesis suggesting that p53 activities other than apoptosis are also critical for tumor suppression. Tumors that arise in these mice are also genomically stable suggesting that the p53R172P mutant transactivates genes involved in maintaining a stable genome. Other mouse models generated probe the importance of components of the p53 pathway. For example, loss of mdm2 or mdm4 (genes that encode p53 inhibitors) results in embryonic lethality that is completely rescued by concomitant loss of p53. These studies indicate the importance of regulating p53 activity. We have made conditional loss-of-function alleles of mdm2 and mdm4 to access the role of p53 in different cell types as a function of proliferation. Finally, we are studying individuals with Li-Fraumeni syndrome, most of whom inherit a p53-missense mutation. Various factors including, modifiers of the p53 pathway alter the onset of tumorigenesis in these individuals.
Program in Genes and Development
Office: MDA BSRB S15.8316B (Unit 1010)
Ph.D. - Rutgers University - 1986