Title: Dynamics of the p53-mdm2 feedback loop in living individual cells, and the design-principles of biological feedback
Speaker: Galit Lahav, Harvard University
Date: Wednesday, March 31, 2004, 1:00 pm
Location: Hill Center, Room 260, Rutgers University, Busch Campus, Piscataway, NJ
A major goal of systems biology is to understand complex protein networks in cells. Great simplification would occur if networks could be broken down into basic recurring circuits, such as the recently defined 'network motifs'. We focused on a common network motif, where a transcription factor is negatively regulated on the protein level by one of its downstream gene products. We employ the well studied p53-mdm2 feedback loop to experimentally study the dynamics of this motif in single living cells. We constructed human cell lines expressing functional p53-CFP and mdm2-YFP fusions. Accurate measurements of protein levels, localizations and interaction were obtained at high temporal resolution by fluorescence microscopy. Detailed oscillatory kinetics following DNA damage was found. We also studied the variability between the dynamics of individual cells, which cannot be seen in assays on cell populations. The results suggest that the p53-Mdm2 feedback loop generates a novel 'digital' clock that releases well-timed quanta of p53 until damage is repaired or the cell dies. We discuss the design-principles of biological feedback that were found in this and other systems.
Seminar sponsored by DIMACS/BIOMAPS Seminar Series on Quantitative Biology and Epidemiology.