title: Stimulus-dependent dynamics of p53 in single cells.
abstract: Many biological networks respond to various inputs through a common signaling molecule that triggers distinct cellular outcomes. One potential mechanism for achieving specific input-output relationships is to trigger distinct dynamical patterns in response to different stimuli. Here we focused on the dynamics of p53, a tumor suppressor activated in response to cellular stress. We quantified the dynamics of p53 in individual cells in response to UV and observed a single pulse that increases in amplitude and duration in proportion to the UV dose. This graded response contrasts with the previously described series of fixed pulses in response to γ-radiation. We further found that while γ-triggered p53 pulses are excitable, the p53 response to UV is not excitable and depends on continuous signaling from the input-sensing kinases. Using mathematical modeling and experiments, we identified feedback loops that contribute to specific features of the stimulus-dependent dynamics of p53, including excitability and input-duration dependency. Our study shows that different stresses elicit different temporal profiles of p53, suggesting that modulation of p53 dynamics might be used to achieve specificity in this network.
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Batchelor
authors.forename: Alexander
authors.initials: A
authors.lastname: Loewer
authors.forename: Caroline
authors.initials: C
authors.lastname: Mock
authors.forename: Galit
authors.initials: G
authors.lastname: Lahav
mesh_terms: D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D025461:Feedback, Physiological; D005720:Gamma Rays; D006801:Humans; D015151:Immunoblotting; D053858:Metabolic Networks and Pathways; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D059010:Single-Cell Analysis; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases