Alcohol intoxication induces a defect in global protein synthetic rates that is localized to impaired translation of mRNA at the level of peptide-chain initiation. Translation initiation is regulated at two steps: formation of the 43S preinitiation

complex [controlled by eukaryotic initiation factors 2 (eIF2) and 2B (eIF2B)] and the binding of mRNA to the 40S ribosome (controlled by the eIF4F complex). To date, alcohol-induced alterations in eIF2 and eIF2B content and activity are best investigated. Ethanol decreases eIF2B activity when ingested AZD7762 datasheet either acutely or chronically. The reduced eIF2B activity most likely is a consequence of twofold increased phosphorylation of the alpha-subunit of eIF2 on Ser(51) following acute intoxication. The increase in eIF2 alpha phosphorylation after chronic alcohol consumption is the same as that induced by acute ethanol intoxication, and protein synthesis is not further reduced by long-term alcohol ingestion despite additional reduced expression of initiation factors and

elongation factors. eIF2 alpha phosphorylation alone appears sufficient to maximally inhibit hepatic protein synthesis. Indeed, pretreatment with Salubrinal, an inhibitor of eIF2 alpha(P) phosphatase, before ethanol treatment does not further inhibit protein synthesis or increase eIF2 alpha phosphorylation, Caspase inhibition suggesting that acute ethanol intoxication causes maximal eIF2 alpha phosphorylation elevation and hepatic protein synthesis inhibition. Ethanol-induced inhibition of hepatic protein synthesis is not rapidly reversed by cessation of ethanol consumption. In conclusion, sustained eIF2 alpha phosphorylation is a hallmark Selleck QNZ of excessive alcohol intake leading to inhibition of protein synthesis. Enhanced phosphorylation of eIF2 alpha represents a unique response of liver to alcohol intoxication, because the ethanol-induced elevation

of eIF2 alpha(P) is not observed in skeletal muscle or heart.”
“The complexity of oestrogen receptor alpha (ER alpha)-mediated transcription is becoming apparent, but global insight into the co-regulatory proteins that assist ER alpha transcription is incomplete. Here, we present the most comprehensive chromatin-binding landscape of ER alpha co-regulatory proteins to date. We map by ChIP-seq the essential p160 co-regulators (SRC1, SRC2 and SRC3), and the histone acetyl transferases p300 and CBP in MCF-7 breast cancer cells. We find a complex network of co-regulator binding, with preferential binding sites for each co-regulator. Unlike previous suggestions, we find SRC recruitment almost exclusively following ligand treatment. Interestingly, we find specific subsets of genes regulated by ligand-dependent and -independent co-regulator recruitment.