Guillermina Lozano
Professor
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.
Publications
- p53R172H and p53R245W Hotspot Mutations Drive Distinct Transcriptomes in Mouse Mammary Tumors Through a Convergent Transcriptional Mediator
- Pancreatic epithelial IL-17/IL-17RA signaling drives B7-H4 expression to promote tumorigenesis
- Inhibition of ULK1/2 and KRAS G12C controls tumor growth in preclinical models of lung cancer
- Mutant p53 protects triple-negative breast adenocarcinomas from ferroptosis in vivo
- p53R245W Mutation Fuels Cancer Initiation and Metastases in NASH-driven Liver Tumorigenesis
- The histone chaperone function of Daxx is dispensable for embryonic development
- Triple-negative breast tumors are dependent on mutant p53 for growth and survival
- Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven by Different p53 Mutants
- Dimeric p53 Mutant Elicits Unique Tumor-Suppressive Activities through an Altered Metabolic Program
- Tissue specificity and spatio-temporal dynamics of the p53 transcriptional program
- Omics analyses of a somatic Trp53R245W/+ breast cancer model identify cooperating driver events activating PI3K/AKT/mTOR signaling
- Modelling aggressive prostate cancers of young men in immune-competent mice, driven by isogenic Trp53 alterations and Pten loss
- Context matters - Daxx and Atrx are not robust tumor suppressors in the murine endocrine pancreas
- p53 Activation Paradoxically Causes Liver Cancer
- Genotype-to-Phenotype Associations in the Aggressive Variant Prostate Cancer Molecular Profile (AVPC-m) Components
Education & Training
Ph.D. - Rutgers University - 1986
Research Info
the p53 tumor suppressor pathway; mouse tumor models