A novel pro-apoptotic function of RACK1: suppression of Src activity in the intrinsic and Akt pathways.
Earlier we showed that RACK1 regulates growth of human colon cells by suppressing Src activity at G(1) 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-X(L), 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 G(1) 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.
Mamidipudi
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Department of Medicine, Stanford University, Stanford, CA 94305-5187, USA.
Cartwright
C A
CA
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D000072224:Bcl-2-Like Protein 11; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000473:pathology*; D045304:Cytochromes c / Q000378:metabolism; D016193:G1 Phase; D019204:GTP-Binding Proteins / Q000502:physiology*; D019073:HT29 Cells; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism; D009363:Neoplasm Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D019311:Staurosporine / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000032:analysis; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D045304:Cytochromes c; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D019204:GTP-Binding Proteins; D019311:Staurosporine