Joint CMU-Pitt Ph.D. Program in Computational Biology Seminar

  • Assistant Professor
  • Department of COmputational and Systems Biology
  • University of Pittsburgh & Hillman Cancer Center

Conservation and divergence in p53 and DNA damage signaling dynamics

The tumor suppressing transcription factor p53 plays a key role in the mammalian DNA damage response and is highly conserved across species and ubiquitously expressed across tissues. However, differential effects on radiosensitivity across tissues, and weak conservation of p53 DNA binding sites across species, suggest divergence of p53 function in both contexts. We combined live imaging of cell lines with measurements of p53 signaling in mouse tissues to study variation in p53 oscillatory period across species and its waveform across tissues and cancer types. By combining these quantitative measurements with mathematical models we can study the aspects of DNA damage signaling that are conserved and tuned by evolution. I will describe how these results inform our understanding of DNA damage signaling, give an example of the limitations of mouse models in DNA damage contexts, and discuss the design of combinations of targeted and genotoxic cancer therapy.

After a brief stint as an analytical chemist researcher (McMaster University), Jacob Stewart-Ornstein has spent the last decade studying stress response signaling, first in budding yeast (as a graduate student at the University of California, SF), more recently in Mammalian Cells (as a postdoc with Dr. Galit Lahav at Harvard Medical School), and finally in his own lab at the University of Pittsburgh. He has shown how using ‘noise’ in gene expression can reveal regulatory networks and how regulation of the key DNA damage factor p53 has changed across evolution and varies across tissues. Jacob’s lab uses quantitative and genomic approaches to study how DNA damage signaling varies across cancers and tissues and how to take advantage of this variation to better and more specifically target cancer cells.

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