Gene/Protein Disease Symptom Drug Enzyme Compound
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 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

S6 kinase 1 (S6K1) acts to integrate nutrient and growth factor signals to promote cell growth but also cell survival as a mitochondria-tethered protein kinase that phosphorylates and inactivates the proapoptotic molecule BAD. Here we report that the prefoldin chaperone URI represents a mitochondrial substrate of S6K1. In growth factor-deprived or rapamycin-treated cells, URI forms stable complexes with protein phosphatase (PP)1gamma at mitochondria, thereby inhibiting the activity of the bound enzyme. Growth factor stimulation induces disassembly of URI/PP1gamma complexes through S6K1-mediated phosphorylation of URI at serine 371. This activates a PP1gamma-dependent negative feedback program that decreases S6K1 activity and BAD phosphorylation, thereby altering the threshold for apoptosis. These findings establish URI and PP1gamma as integral components of an S6K1-regulated mitochondrial pathway dedicated, in part, to oppose sustained S6K1 survival signaling and to ensure that the mitochondrial threshold for apoptosis is set in accord with nutrient and growth factor availability.
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PMID:S6K1-mediated disassembly of mitochondrial URI/PP1gamma complexes activates a negative feedback program that counters S6K1 survival signaling. 1793 2

Although the ultimate outcome of prolonged exposure of cells to stress is often death, the early response appears to be the activation of survival pathways that are likely to give the cell an opportunity to repair low-level damage. How these stress-initiated survival pathways influence B cell lymphoma/leukemia 2 (Bcl-2) proteins, the core cell death machinery, has remained unclear; however, two papers now provide insight into stress-mediated survival mechanisms. The liver is unusually resistant to p53-mediated apoptosis. It appears that p53-mediated induction of the gene that encodes insulin-like growth factor-binding protein-1 (IGFBP1) attenuates the cell death response in hepatocytes by preventing the formation of a complex between p53 and the proapoptotic protein BAK. This is especially interesting as IGFBP1 is not a member of the Bcl-2 family, yet it inhibited BAK. In three unrelated cell lines, another regulatory interaction that influences cell survival occurs at the mitochondria. In this case, protein phosphatase 1gamma (PP1gamma) regulated the phosphorylation status of the Bcl-2/Bcl-X(L)-associated death promoter (BAD). The prefoldin family member URI is normally phosphorylated by S6 kinase 1, which liberates PP1gamma from a URI-PP1gamma complex. However, the withdrawal of growth factors or nutrients stabilizes this complex, which renders PP1gamma inactive. The net response of this stress stimulus is an increased abundance of phosphorylated BAD, which raises the threshold required to trigger cell death. These two studies have identified new players and mechanisms that integrate stress responses and cell death.
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PMID:Cell stress gives a red light to the mitochondrial cell death pathway. 1828 8

URI (unconventional prefoldin RPB5 interactor protein) is an unconventional prefoldin, RNA polymerase II interactor that functions as a transcriptional repressor and is part of a larger nuclear protein complex. The components of this complex and the mechanism of transcriptional repression have not been characterized. Here we show that KAP1 (KRAB-associated protein 1) and the protein phosphatase PP2A interact with URI. Mechanistically, we show that KAP1 phosphorylation is decreased following recruitment of PP2A by URI. We functionally characterize the novel URI-KAP1-PP2A complex, demonstrating a role of URI in retrotransposon repression, a key function previously demonstrated for the KAP1-SETDB1 complex. Microarray analysis of annotated transposons revealed a selective increase in the transcription of LINE-1 and L1PA2 retroelements upon knockdown of URI. These data unveil a new nuclear function of URI and identify a novel post-transcriptional regulation of KAP1 protein that may have important implications in reactivation of transposable elements in prostate cancer cells.
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PMID:URI Regulates KAP1 Phosphorylation and Transcriptional Repression via PP2A Phosphatase in Prostate Cancer Cells. 2778 Aug 69