Cell-to-Cell Heterogeneity in p38-Mediated Cross-Inhibition of JNK Causes Stochastic Cell Death.
The stress-activated protein kinases c-Jun N-terminal kinase (JNK) and p38 are important players in cell-fate decisions in response to environmental stress signals. Crosstalk signaling between JNK and p38 is emerging as an important regulatory mechanism in inflammatory and stress responses. However, it is unknown how this crosstalk affects signaling dynamics, cell-to-cell variation, and cellular responses at the single-cell level. We established a multiplexed live-cell imaging system based on kinase translocation reporters to simultaneously monitor JNK and p38 activities with high specificity and sensitivity at single-cell resolution. Various stresses activated JNK and p38 with various dynamics. In all cases, p38 suppressed JNK activity in a cross-inhibitory manner. We demonstrate that p38 antagonizes JNK through both transcriptional and post-translational mechanisms. This cross-inhibition generates cellular heterogeneity in JNK activity after stress exposure. Our data indicate that this heterogeneity in JNK activity plays a role in fractional killing in response to UV stress.
['Miura|Haruko|H|', 'Kondo|Yohei|Y|', 'Matsuda|Michiyuki|M|', 'Aoki|Kazuhiro|K|']
D017209:Apoptosis D016923:Cell Death D054638:Dual Specificity Phosphatase 1 D006801:Humans D048031:JNK Mitogen-Activated Protein Kinases D020935:MAP Kinase Signaling System D020928:Mitogen-Activated Protein Kinases D061848:Optical Imaging D015398:Signal Transduction D014466:Ultraviolet Rays D048051:p38 Mitogen-Activated Protein Kinases
cross-inhibition JNK p38 stress DUSP1 KTR cell-to-cell variability fluorescence imaging