Survival signaling by C-RAF: mitochondrial reactive oxygen species and Ca2+ are critical targets.

Molecular and Cellular Biology
Andrey V KuznetsovJakob Troppmair

Abstract

Survival signaling by RAF occurs through largely unknown mechanisms. Here we provide evidence for the first time that RAF controls cell survival by maintaining permissive levels of mitochondrial reactive oxygen species (ROS) and Ca(2+). Interleukin-3 (IL-3) withdrawal from 32D cells resulted in ROS production, which was suppressed by activated C-RAF. Oncogenic C-RAF decreased the percentage of apoptotic cells following treatment with staurosporine or the oxidative stress-inducing agent tert-butyl hydroperoxide. However, it was also the case that in parental 32D cells growing in the presence of IL-3, inhibition of RAF signaling resulted in elevated mitochondrial ROS and Ca(2+) levels. Cell death is preceded by a ROS-dependent increase in mitochondrial Ca(2+), which was absent from cells expressing transforming C-RAF. Prevention of mitochondrial Ca(2+) overload after IL-3 deprivation increased cell viability. MEK was essential for the mitochondrial effects of RAF. In summary, our data show that survival control by C-RAF involves controlling ROS production, which otherwise perturbs mitochondrial Ca(2+) homeostasis.

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Citations

Feb 22, 2011·Analytical and Bioanalytical Chemistry·Andrey V KuznetsovJakob Troppmair
Mar 20, 2010·Cell Death and Differentiation·C E EdgarR J Bram
Aug 21, 2008·Cell Communication and Signaling : CCS·Martin HermannJakob Troppmair
May 27, 2009·International Journal of Molecular Sciences·Andrey V Kuznetsov, Raimund Margreiter
Jan 16, 2014·Cell Communication and Signaling : CCS·Muhammad Imtiaz AshrafJakob Troppmair
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Oct 22, 2014·The FEBS Journal·Su AnTian-Rui Xu
Dec 6, 2014·Basic Research in Cardiology·Rita FerreiraRui Vitorino
Apr 7, 2018·Molecular Oncology·Tobias FurlanJakob Troppmair
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