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

Oncogene volume 27, pages 2430–2444 (2008)Cite this article

Abstract

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-κB) 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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Abbreviations

AIF:

apoptotic-inducing factor

CBP:

CREB-binding protein

IκB:

inhibitor of NF-κB

p53:

tumor-suppressor protein

RAC3:

receptor-associated co-activator-3

SRC-1:

steroid receptor co-activator-1

TIF-2:

transcriptional intermediary factor-2

TNF-α:

tumor necrosis factor-α

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Acknowledgements

We thank Dr Roberto Rosato and Dr Steven Grant for comments about the manuscript and Dr Fernanda Ceriani for help and support. This work has been supported by grants from the Argentine National Research Council (CONICET), Agencia Nacional de Promoción Científica y Tecnológica and Fundación Antorchas, Argentina and the NIH Fogarty International Center Grant R03TW007162-01A2.

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  1. M D Galigniana and M A Costas: Member of the Argentine National Research Council (CONICET), Buenos Aires, Argentina.

Authors and Affiliations

  1. 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

    G P Colo, M F Rubio, I M Nojek, S E Werbajh, P C Echeverría, C V Alvarado, V E Nahmod & M A Costas

  2. Laboratorio de Receptores Nucleares y Arquitectura Nuclear, Fundación Instituto Leloir, Buenos Aires, Argentina

    M D Galigniana

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  1. G P Colo
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Correspondence to M A Costas.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Colo, G., Rubio, M., Nojek, I. et al. The p160 nuclear receptor co-activator RAC3 exerts an anti-apoptotic role through a cytoplasmatic action. Oncogene 27, 2430–2444 (2008). https://doi.org/10.1038/sj.onc.1210900

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