Endoplasmic reticulum (ER) stress is emerging as a potential contributor to the onset of type 2 diabetes by making cells insulin-resistant. However, our understanding of the mechanisms by which ER stress affects insulin response remains fragmentary. Here we present evidence that the ER stress pathway acts via a conserved signaling mechanism involving the protein kinase PERK to modulate cellular insulin responsiveness. Insulin signaling via AKT reduces activity of FOXO transcription factors. In some cells, PERK can promote insulin responsiveness. However, we found that PERK also acts oppositely via phosphorylation of FOXO to promote FOXO activity. Inhibition of PERK improves cellular insulin responsiveness at the level of FOXO activity. We suggest that the protein kinase PERK may be a promising pharmacological target for ameliorating insulin resistance.

A series of ternary copper(II) complexes of the type [Cu^II(L)(M)]²⁺, where M represents the hexapeptides GGGFLR, YGGFLR and WGGFLR and L a set of 12 nitrogen donor ligands have been evaluated for their ability to form cationic peptide radicals, M⁺˙, in the gas phase. Although the fragmentation chemistry of these ions is complex, two main conclusions emerge: (i) Complexes containing a tri- or tetra-dentate ligand were found to be more effective at producing the peptide radical because in these instances competitive loss of the ligand from the complex is inhibited; (ii) The ligands ought not possess any acidic protons in order to prevent competitive loss of the protonated peptide, [M + H]⁺. There is significant interaction of the N-terminal aromatic residues in YGGFLR and WGGLFR with the copper(II) ion in several of the complexes as revealed by the formation of [Cu^I(L)(p-quinomethide)]⁺ and [Cu^I(L)(3-methyleneindoline)]⁺ fragment ions. Following its dissociation from the ternary complex, CID of the YGGFLR⁺˙ radical cation shows a dependence on the ligand in the complex from which it was formed. This ‘memory effect’ most likely reflects differences in the coordinated peptide structure induced by the ligand in the precursor complex which are maintained following dissociation.

Degradation of p53 is a cornerstone in the control of its functions as a tumor suppressor. This process is attributed to ubiquitin-dependent modification of p53. In addition to polyubiquitination, ...