A novel pro-apoptotic function of rack1: suppression of src activity in the intrinsic and akt pathways

ABSTRACT Earlier we showed that RACK1 regulates growth of human colon cells by suppressing Src activity at G1 and mitotic checkpoints. Here, we show that RACK1 also induces apoptosis of the

cells, partly by inhibiting Src. In the intrinsic pathway, RACK1 inhibits expression of anti-apoptotic Bcl-2 and Bcl-XL, induces expression of pro-apoptotic Bim, targets Bim and Bax to the

mitochondria, induces oligomerization of Bax (which requires Bim and inhibition of Src), depolarizes mitochondria membranes, releases cytochrome _c_, and activates caspases-9 and -3 and

death substrates. Bax and Bim are required for RACK1-mediated mitochondrial cell death. RACK1-induced oligomerization of Bax is required for staurosporine-mediated cell death. RACK1 also

induces apoptosis by blocking Src activation of the Akt cell survival pathway. This leads to activation of the transcription factor FOXO3, a potent inducer of apoptosis and G1 arrest.

Collectively, our results show that RACK1, partly by inhibiting Src, promotes mitochondrial cell death and blocks Akt-mediated cell survival. Thus, RACK1 inhibits growth and induces death of

colon cells. Exploitation of these dual functions could lead to novel colon cancer therapies that mimic RACK1 function. Access through your institution Buy or subscribe This is a preview of

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regulates cell survival and apoptosis at a postmitochondrial level. _J Cell Biol_ 151: 483–494. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We thank Jenny Cheng and

Gayathri Swaminathan for many helpful discussions and critical review of the data and manuscript. This work was supported by a grant from the National Institutes of Health to CAC (DK43743).

Preliminary studies were supported by a pilot grant from the Broad Medical Research Program (IBD-0068). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Medicine, Stanford

University, Stanford, CA, USA V Mamidipudi & C A Cartwright Authors * V Mamidipudi View author publications You can also search for this author inPubMed Google Scholar * C A Cartwright

View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to C A Cartwright. ADDITIONAL INFORMATION Supplementary Information

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THIS ARTICLE CITE THIS ARTICLE Mamidipudi, V., Cartwright, C. A novel pro-apoptotic function of RACK1: suppression of Src activity in the intrinsic and Akt pathways. _Oncogene_ 28, 4421–4433

(2009). https://doi.org/10.1038/onc.2009.293 Download citation * Received: 28 May 2009 * Revised: 12 August 2009 * Accepted: 23 August 2009 * Published: 21 September 2009 * Issue Date: 17

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link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * RACK1 * Src * apoptosis * mitochondrial

cell death * intrinsic pathway * Akt cell survival pathway