My lab seeks to develop a quantitative, system-level understanding of stress response pathways at multiple scales -- from individual cells to whole organisms. Much of our research focuses on cell stress responses mediated by the tumor suppressor protein p53. We have used long-term time-lapse imaging to show that p53 undergoes complex dynamics in response to different forms of DNA damage. For example, in response to DNA double-strand breaks p53 levels increase and decrease in oscillations of fixed amplitude, duration, and frequency. In contrast, in response to UV-induced DNA damage p53 levels increased in a single pulse with a duration and amplitude that increases with decreasing damage. We have identified the specific molecular mechanisms that regulate the distinct p53 dynamical modes. By using small molecule inhibitors to alter p53 dynamics, we can change the transcriptional program regulated by p53 and thereby control individual cell fates.
Our current work focuses on developing a more integrated, network-level view of the regulation and function of p53 dynamics in single cells. We focus on identifying the molecular details by which p53 dynamics regulate downstream damage response pathways, including those regulating cell cycle arrest, DNA repair, senescence, apoptosis, and metabolism. We aim to identify how specific p53 pulse characteristics (amplitude, duration, or frequency) encode information that is decoded at the promoters of transcriptional targets. We are also applying quantitative, single-cell approaches to identify novel modes of regulation between p53 and other important signaling pathways, including the MYC proto-oncogene network and MAPK signaling. By developing a more quantitative understanding of these important signaling pathways, we hope to not only increase our basic understanding of these signaling dynamics in regulating cell fate decisions, but also provide novel methods for chemotherapeutic manipulation of signaling dynamics to alter cell fate in cancers in which the pathways are deregulated.
Honors and Recognition
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