Oscillations by the p53-Mdm2 feedback loop.
The p53 network is perhaps the most important pathway involved in preventing the initiation of cancer, p53 levels and activity are upregulated in response to various stresses including DNA damage, hypoxia, and oncogene activation. Active p53 initiates different transcriptional programs that result in cell cycle arrest, cellular senescence or apoptosis. p53 also activates the transcription of Mdm2, which in turns target p53 for degradation, therefore creating a negative feedback loop on p53. Previous studies showed that the level of p53 increased dramatically after exposure to damaging radiation, then declined in a series of damped oscillations. Recent quantitative studies examined p53 responses in individual living cells, using time-lapse fluorescent microscopy and showed that-on an individual cell level-the oscillations are not damped. Instead, one cell may have only one pulse of p53, while its neighbor may show several repeated pulses. As the amount of irradiation increased, the percentage of cells showing a high number of p53 pulses also increased. The mean height and width of the pulses was constant and did not depend on the damage level. These observations opened new questions regarding the mechanism and function of p53 oscillatory dynamics. In this chapter I will review the different models that have been suggested for p53 oscillations, including proposed reasons for variation between cells, and will discuss potential functions for oscillatory dynamics in the p53 signaling pathway and in stress responses in general.
Lahav
Galit
G
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. galit@hms.harvard.edu
D001683:Biological Clocks; D004249:DNA Damage; D025461:Feedback, Physiological; D006801:Humans; D008954:Models, Biological; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2