The p160 nuclear receptor co-activator RAC3 exerts an anti-apoptotic role through a cytoplasmatic action.
The p160 nuclear receptor co-activators represent a family of molecules, which are recruited by steroid nuclear receptors as well as other transcription factors that are overexpressed in several tumors. We investigated the role of one member of this family on the sensitivity of cells to apoptosis. We observed that overexpression of the RAC3 (receptor-associated co-activator-3) p160 co-activator inhibits hydrogen peroxide-induced cell death in human embryonic kidney 293 (HEK293) cells. The mechanism involves the activation of anti-apoptotic pathways mediated through enhanced nuclear factor kappa B (NF-kappaB) activity, inhibition of caspase-9 activation, diminished apoptotic-inducing factor (AIF) nuclear localization and a change in the activation pattern of several kinases, including an increase in both AKT and p38 kinase activities, and inhibition of ERK2. Moreover, RAC3 has been found associated with a protein complex containing AIF, Hsp90 and dynein, suggesting a role for the co-activator in the cytoplasmatic nuclear transport of these proteins associated with cytoskeleton. These results demonstrate that there are several molecular pathways that could be affected by their overexpression, including those not restricted to steroid regulation or the nuclear action of co-activators, which results in diminished sensitivity to apoptosis. Furthermore, this could represent one mechanism by which co-activators contribute to tumor development.
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Laboratorio de Biología Molecular y Apoptosis, Instituto de Investigaciones Médicas Alfredo Lanari (IDIM)-Argentine National Research Council (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina.
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Nojek
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Werbajh
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Echeverría
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Alvarado
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Nahmod
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Galigniana
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D021581:Active Transport, Cell Nucleus; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism*; D004398:Dyneins / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D051033:Apoptosis Inducing Factor; D018841:HSP90 Heat-Shock Proteins; D016328:NF-kappa B; C411563:RAC3 protein, human; D006861:Hydrogen Peroxide; D011494:Protein Kinases; D053453:Caspase 9; D004398:Dyneins; D020744:rac GTP-Binding Proteins; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4