MDA S15.8316B (Unit 1010)
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.
- 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
- Is loss of p53 a driver of ductal carcinoma in situ progression?
- EGFR suppresses p53 function by promoting p53 binding to DNA-PKcs: a noncanonical regulatory axis between EGFR and wild-type p53 in glioblastoma
- Differential Gain-of-Function Activity of Three p53 Hotspot Mutants In Vivo
- Alterations of the Mdm2 C-Terminus Differentially Impact Its Function In Vivo
- Analysis of Population Differences in Digital Conversations About Cancer Clinical Trials: Advanced Data Mining and Extraction Study
- Mammary-specific expression of Trim24 establishes a mouse model of human metaplastic breast cancer
- A Blood-based Polyamine Signature Associated With MEN1 Duodenopancreatic Neuroendocrine Tumor Progression
Education & Training
Ph.D. - Rutgers University - 1986
the p53 tumor suppressor pathway; mouse tumor models