Cell Reports
Volume 24, Issue 10, 4 September 2018, Pages 2658-2668
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Article
Cell-to-Cell Heterogeneity in p38-Mediated Cross-Inhibition of JNK Causes Stochastic Cell Death

https://doi.org/10.1016/j.celrep.2018.08.020Get rights and content
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Highlights

  • A multiplexed live-cell imaging system visualizes suppression of JNK by p38 kinase

  • Cross-inhibition of JNK by p38 generates cell-to-cell heterogeneity in JNK activity

  • p38-induced DUSP1 expression is inversely correlated with JNK activity in single cells

  • Heterogeneity in JNK activity is associated with fractional killing upon UV stress

Summary

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.

Keywords

JNK
p38
DUSP1
cross-inhibition
fluorescence imaging
KTR
cell-to-cell variability
stress

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