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Phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) by the kinase GCN2 attenuates protein synthesis during amino acid starvation in yeast, whereas in mammals a family of related eIF2α kinases regulate translation in response to a variety of stresses. Unlike single-celled eukaryotes, mammals also possess two specific eIF2α(More)
Endoplasmic reticulum (ER) stress is an integral part of life for all professional secretory cells, but it has been studied to greatest depth in the pancreatic β-cell. This reflects both the crucial role played by ER stress in the pathogenesis of diabetes and also the exquisite vulnerability of these cells to ER dysfunction. The adaptive cellular response(More)
Mutations in the tau gene (MAPT) have been found in families with frontotemporal dementia with parkinsonism linked to chromosome 17. In addition, the MAPT H1-clade specific sub-haplotype, H1c, has been strongly associated with the tauopathies, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) and, to a lesser extent, with Alzheimer's(More)
Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas with poor prognosis and limited treatment options. Evidence for a role of epidermal growth factor receptor (EGFR) and receptor tyrosine kinase erbB2 in MPNSTs led us to systematically study these potential therapeutic targets in a larger tumor panel (n = 37). Multiplex ligation-dependent probe(More)
We identified a case of Alzheimer's disease with a deletion of the lysine residue at codon 280 (DeltaK280) in exon 10-encoded microtubule-binding repeat domain of the tau gene (MAPT). This mutation was originally identified in a sporadic case of frontotemporal dementia (FTD) with a family history of Parkinson's disease. In the original report, the authors(More)
A subset of glioblastomas (GBMs) carry gene amplifications on chromosomal segment 4q12. To characterize this amplicon in detail, we analyzed a set of 100 samples consisting of 65 GBMs, 10 WHO grade III astrocytomas, 12 oligodendrogliomas, and 13 glioma cell cultures. We applied multiplex ligation-dependent probe amplification to determine the gene dosage of(More)
Cell cycle checkpoints ensure that proliferation occurs only under permissive conditions, but their role in linking nutrient availability to cell division is incompletely understood. Protein folding within the endoplasmic reticulum (ER) is exquisitely sensitive to energy supply and amino acid sources because deficiencies impair luminal protein folding and(More)
The integrated stress response (ISR) protects cells from numerous forms of stress and is involved in the growth of solid tumours; however, it is unclear how the ISR acts on cellular proliferation. We have developed a model of ISR signalling with which to study its effects on tissue growth. Overexpression of the ISR kinase PERK resulted in a striking(More)
Mutants of neuroserpin are retained as polymers within the endoplasmic reticulum (ER) of neurones to cause the autosomal dominant dementia familial encephalopathy with neuroserpin inclusion bodies or FENIB. The cellular consequences are unusual in that the ordered polymers activate the ER overload response (EOR) in the absence of the canonical unfolded(More)
Four stress-sensing kinases phosphorylate the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) to activate the integrated stress response (ISR). In animals, the ISR is antagonised by selective eIF2α phosphatases comprising a catalytic protein phosphatase 1 (PP1) subunit in complex with a PPP1R15-type regulatory subunit. An unbiased search(More)