Journal
NATURE COMMUNICATIONS
Volume 5, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/ncomms6777
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Funding
- GIST Systems Biology Infrastructure Establishment Grant
- National Research Foundation of Korea (NRF) - Korea Government, the Ministry of Science, ICT and Future Planning [2010-0017662, 2014R1A2A1A10052404, 2013M3A9A7046303, 2013M3A9A7046297]
- KAIST Future Systems Healthcare Project from the Ministry of Science, ICT and Future Planning
- BK21 Plus program from the Ministry of Education of Korea
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How cell fate (survival or death) is determined and whether such determination depends on the strength of stimulation has remained unclear. In this study, we discover that the cell fate of cardiomyocytes switches from survival to death with the increase of beta-adrenergic receptor (beta-AR) stimulation. Mathematical simulations combined with biochemical experimentation of beta-AR signalling pathways show that the gradual increment of isoproterenol (a non-selective beta 1/beta 2-AR agonist) induces the switching response of Bcl-2 expression from the initial increase followed by a decrease below its basal level. The ERK1/2 and ICER-mediated feed-forward loop is the hidden design principle underlying such cell fate switching characteristics. Moreover, we find that beta 1-blocker treatment increases the survival effect of beta-AR stimuli through the regulation of Bcl-2 expression leading to the resistance to cell death, providing new insight into the mechanism of therapeutic effects. Our systems analysis further suggests a novel potential therapeutic strategy for heart disease.
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