Guillermina (Gigi) Lozano, Ph.D.

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 allele 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.

Recent publications

Grier, J.D., Xiong, S, Elizondo-Fraire, A.C., Parant, J.M., and Lozano, G. (2006) Tissue specific differences of p53 inhibition by Mdm2 and Mdm4. Mol. Cell. Biol. 26:192-198.
Xiong, S., Van Pelt, C.S., Elizondo-Fraire, A.C., Liu, G., and Lozano, G. (2006) Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development. Proc. Natl. Acad. Sci. USA., 103:3226-3231.
Lang, G.A., Iwakuma, T., Suh, Y.A., Liu, G., Rao, V.A., Parant, J.M., Valentin-Vega, Y.A., Terzian, T., Caldwell, L.C., Strong, L.C., El-Naggar, A.K. and Lozano, G. (2004) Gain-of-function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 119:861–872.
Bond, G.L., Hu, W., Bond, E.E., Robins, H., Bartel, F., Taubert, H., Wuerl, P., Onel, K., Yip, L., Hwang, S.J., Strong, L.C., Lozano, G. and Levine, A.J. (2004) A single nucleotide polymorphism in the mdm2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119:591–602.
Liu, G., Parant, J.M., Lang, G., Chau, P., Chavez-Reyes, A., El-Naggar, A.K., Multani, A., Chang, S. and Lozano, G. (2004) Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat. Genet. 36:63–68.
Hwang, S.J., Lozano, G., Amos, C.I. and Strong L.C. (2003) Germline p53 mutations in a cohort with childhood sarcoma: Sex differences in cancer risk. Amer. J. Hum. Genet. 72:975–983.
Parant, J., Chavez-Reyes, A., Little, N.A., Yan, W., Reinke, V., Jochemsen, A.G. and Lozano, G. (2001) Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nature Genetics 29:92–95.
Liu G, McDonnell TJ, Montes de Oca Luna R, Kapoor M, Mims B, El-Naggar AK, Lozano G (2000) High metastatic potential in mice inheriting a targeted p53 missense mutation. Proc Natl Acad Sci USA 97:4174–4179.
Montes de Oca Luna R, Wagner DS, Lozano G (1995) Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378:203–206.