Attardi Lab Research
The p53 gene is the most commonly mutated gene in human cancer, displaying mutations in at least half of all human cancers. In addition, p53 null mice develop cancer at 100% frequency. Together, these findings underscore the critical role for the p53 protein in tumor suppression. Notably, p53 is commonly mutated in cancers by missense mutation, leading to retention of a mutant protein that also exerts gain-of-function effects. Thus, p53 mutation causes loss of normal function and gain of new properties that promote cancer development.
p53 is a cellular stress sensor, responding to diverse insults such as DNA damage, hyperproliferative signals, and hypoxia by inducing growth arrest or apoptosis, responses thought to be important to tumor suppression. In addition, as a cellular stress sensor, p53 plays both physiological and pathological roles beyond tumor suppression. For example, p53 plays beneficial roles such as promoting fertility, and induces detrimental phenotypes in certain situations such as the side effects of cancer therapies or the cell death observed during stroke or neurodegenerative disease. The overarching goal of our research is to better define the mechanisms by which the p53 protein promotes different responses in different settings, ranging from tumor suppression to responses to chemotherapeutics, using the mouse as an in vivo model system. This understanding will help us understand how to best promote the beneficial and minimize the detrimental effects of p53 in the clinic.
We utilize a combination of mouse genetic, cell biological, biochemical, and genomic approaches to address understand how p53 acts and to use this knowledge for therapeutic benefit. We have a number of areas of investigation, as illustrated below. These include:
• Identifying the transcriptional networks responsible for tumor suppression, using CRISPR/Cas9 and shRNA screening approaches and mass spectrometry approaches
• Examining mechanisms of p53 gain of function properties in cancer
• Elucidating the genes activated and repressed by p53 in diverse settings using genomic technologies such as ChIP-sequencing and RNA-sequencing, to understand how p53 drives different responses
• Identifying p53 inhibitors to find strategies to inhibit the detrimental effects of p53 activation, such as during cancer therapy
• Understanding p53’s role in developmental diseases such as CHARGE syndrome
• Characterizing p53-regulated noncoding RNAs and their roles in cancer
Using these combined approaches, we aim to derive a comprehensive picture of this remarkable molecule and to learn how to best modulate it during the treatment of cancer and other diseases.
Perp, a p53/p63 target gene | p53 targets in apoptosis | p53 knock-in mice