The p160 nuclear receptor co-activator RAC3 exerts an anti-apoptotic role through a cytoplasmatic action

Abstract

The p160 nuclear receptor coactivators represent a family of molecules, which are recruited by steroid nuclear receptors as well as other transcription factors that are over-expressed in several tumors. We investigated the role of one member of this family on the sensitivity of cells to apoptosis. We observed that over-expression of the RAC3 p160 coactivator inhibits hydrogen peroxide-induced cell death in HEK293 cells. The mechanism involves the activation of anti-apoptotic pathways mediated through enhanced NF-kB activity, inhibition of caspase-9 activation, diminished AIF nuclear localization and the change in the activation pattern of several kinases, including the increase in both AKT and p38 kinases activities, and inhibition of ERK2. Moreover, RAC3 has been found associated to a protein complex containing AIF, Hsp90 and dynein, suggesting a role for the coactivator in the cytoplasmatic-nuclear-transport of these proteins associated to cytoskeleton. These results demonstrate that there are several molecular pathways that could be affected by their over-expression, including those not restricted to steroid regulation or the nuclear action of coactivators, which results in diminished sensitivity to apoptosis. Furthermore, this could represent one mechanism by which coactivators contribute to tumor development.