Post-translational modification of p53 and the integration of stress signals.
The p53 tumour suppressor protein is a potent transcription factor. p53 is latent in cells and can be activated in response to signals arising from a range of stresses including DNA damage, hypoxia, nucleotide depletion, viral infection and cytokines. Activation of p53 leads either to cellular growth arrest at the G1/S or G2/M transitions of the cell cycle or to programmed cell death (apoptosis). The mechanism of activation of p53 is poorly understood, as are the factors which govern the decision between growth arrest or apoptosis. However, accumulating evidence points to a role for multi-site phosphorylation of p53 in mediating these events. p53 is phosphorylated at different sites within its N-terminal domain by protein kinases which are responsive to UV radiation, cytokines, DNA damage and growth factors. At the C-terminus p53 is phosphorylated by protein kinases involved in growth stimulation, cell cycle control and apoptosis. While little is yet understood about the role of phosphorylation at the N-terminal sites, the C-terminal phosphorylation events are each involved in controlling the specific DNA binding function of p53, perhaps in a coordinate manner, and may also play a role in regulating other functions of p53 such as DNA strand annealing and transcriptional repression. Understanding the control of p53 by multisite phosphorylation may therefore provide essential information concerning the mechanisms of activation of p53, the biological consequences of this activation, and the role of p53 as an integrator of stress signals.
Meek
D W
DW
Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom.
D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000503:physiopathology*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D011493:Protein Kinase C