p53 dynamics control cell fate.
Cells transmit information through molecular signals that often show complex dynamical patterns. The dynamic behavior of the tumor suppressor p53 varies depending on the stimulus; in response to double-strand DNA breaks, it shows a series of repeated pulses. Using a computational model, we identified a sequence of precisely timed drug additions that alter p53 pulses to instead produce a sustained p53 response. This leads to the expression of a different set of downstream genes and also alters cell fate: Cells that experience p53 pulses recover from DNA damage, whereas cells exposed to sustained p53 signaling frequently undergo senescence. Our results show that protein dynamics can be an important part of a signal, directly influencing cellular fate decisions.
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
Jeremy E
JE
Purvis
Kyle W
KW
Karhohs
Caroline
C
Mock
Eric
E
Batchelor
Alexander
A
Loewer
Galit
G
Lahav
D017209:Apoptosis / Q000235:genetics; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D005720:Gamma Rays; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D000071156:Promyelocytic Leukemia Protein; D015398:Signal Transduction; D059010:Single-Cell Analysis; D014157:Transcription Factors / Q000235:genetics; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007093:Imidazoles; D009687:Nuclear Proteins; D010879:Piperazines; D000071156:Promyelocytic Leukemia Protein; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C482205:nutlin 3