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Tissue-type plasminogen activator rescues neurones from serum deprivation-induced apoptosis through a mechanism independent of its proteolytic activity

Abstract : Although the mechanism of action of tissue-type plasmino-gen activator (tPA) in excitotoxic necrosis is well documented , whether this serine protease can influence the apoptotic cascade remains a subject of debate. Here, we report that tPA protects cultured cortical neurones against apoptotic cell death induced by serum deprivation, an effect associated with a reduction of caspase-3 activation. Interestingly , blocking tPA proteolytic activity by either tPA stop or neuroserpin did not prevent this neuroprotection. Similarly , prevention of the interaction between tPA and its receptor low-density lipoprotein receptor-related protein (LRP) could not alter tPA anti-apoptotic activity. Interestingly , the survival-promoting effect of tPA was blocked by the phosphatidylinositol-3 (PI-3) kinase inhibitor, LY294002, but not by the mitogen-activated protein (MAP) kinase inhibitor, U0126. In conclusion, the present demonstration of an anti-apoptotic effect of tPA, independent of its enzymatic activity, reveals an additional level of complexity in our understanding of this critical mediator of brain physiology and pathology. Keywords: apoptosis, serine protease, serum deprivation, tissue-type plasminogen activator.
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https://www.hal.inserm.fr/inserm-01296667
Contributor : Benoit Roussel <>
Submitted on : Friday, April 1, 2016 - 1:44:01 PM
Last modification on : Sunday, December 15, 2019 - 2:30:04 PM
Long-term archiving on: : Monday, November 14, 2016 - 12:02:18 PM

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Géraldine Liot, Benoit Roussel, Nathalie Lebeurrier, Karim Benchenane, Denis Vivien, et al.. Tissue-type plasminogen activator rescues neurones from serum deprivation-induced apoptosis through a mechanism independent of its proteolytic activity. Journal of Neurochemistry, Wiley, 2006, ⟨10.1111/j.1471-4159.2006.03982.x⟩. ⟨inserm-01296667⟩

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