Dynamic 14-3-3/client protein interactions integrate survival and apoptotic pathways.
The serine/threonine binding protein, 14-3-3, possesses a diverse array of client proteins. It is involved in the regulation of apoptosis through multiple interactions with proteins of the core mitochondrial machinery, pro-apoptotic transcription factors, and their upstream signaling pathways. 14-3-3 coordinates with survival kinases to inhibit multiple pro-apoptotic molecules. One prominent mechanism for the suppression of apoptosis is through 14-3-3-mediated sequestration of pro-apoptotic client proteins. On the other hand, cellular stresses appear to signal through the inhibition of 14-3-3 function to exert their pro-apoptotic effect. Global inhibition of 14-3-3/client protein interaction induces apoptosis, and stands as an attractive intervention in diseases involving overactive survival signaling pathways. Because dysregulation of 14-3-3 has been associated with poor survival of cancer patients, targeting 14-3-3 may provide a novel therapeutic approach for the treatment of cancer.
Porter
Gavin W
GW
Department of Pharmacology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. gporter@emory.edu
Khuri
Fadlo R
FR
Fu
Haian
H
D048948:14-3-3 Proteins / Q000187:drug effects / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D002470:Cell Survival; D006801:Humans; D008024:Ligands; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2; D017346:Protein Serine-Threonine Kinases; D020169:Caspases