The p160 nuclear receptor co-activator RAC3 exerts an anti-apoptotic role

COLO GP, RUBIO MF, NOJEK IM, WERBAJH SE, ECHEVERRÍA PC, ALVARADO CV, NAHMOD VE, GALIGNIANA MD, COSTAS MA

ONCOGENE

NATURE PUBLISHING GROUP

Año: 2008 vol. 27 p. 2430 - 2444

0950-9232

The p160 nuclear receptor co-activators represent a familyof 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 familyon the sensitivityof 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 (NFjB) 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 coactivator in the cytoplasmatic nuclear transport of these proteins associated with cytoskeleton. These results demonstrate that there are several molecular pathways that could be affected bytheir overexpression, including those not restricted to steroid regulation or the nuclear action of co-activators, which results in diminished sensitivityto apoptosis. Furthermore, this could represent one mechanism bywhich co-activators contribute to tumor development.jB) 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 coactivator in the cytoplasmatic nuclear transport of these proteins associated with cytoskeleton. These results demonstrate that there are several molecular pathways that could be affected bytheir overexpression, including those not restricted to steroid regulation or the nuclear action of co-activators, which results in diminished sensitivityto apoptosis. Furthermore, this could represent one mechanism bywhich co-activators contribute to tumor development.