Elevation of proteasomal substrate levels sensitizes cells to apoptosis induced by inhibition of proteasomal deubiquitinases.

Inhibitors of the catalytic activity of the 20S proteasome are cytotoxic to tumor cells and are currently in clinical use for treatment of multiple myeloma, whilst the deubiquitinase activity associated with the 19S regulatory subunit of the proteasome is also a valid target for anti-cancer drugs. The mechanisms underlying the therapeutic efficacy of these drugs and their selective toxicity towards cancer cells are not known. Here, we show that increasing the cellular levels of proteasome substrates using an inhibitor of Sec61-mediated protein translocation significantly increases the extent of apoptosis that is induced by inhibition of proteasomal deubiquitinase activity in both cancer derived and non-transformed cell lines.

Epidemiology of lysosomal storage diseases in Sweden.

Aim: There are more than 50 inherited lysosomal storage diseases (LSDs), and this study examined the incidence of clinically diagnosed LSDs in Sweden.

Methods: The number of patients diagnosed during 1980-2009 was compiled from the registries of the two Swedish diagnostic laboratories that cover the whole country.

Results: We identified 433 patients during the 30-year period, with a total incidence of one in every 6100 births and identified fairly constant annual diagnoses during the last 20 years.

The HOG pathway dictates the short-term translational response after hyperosmotic shock.

Cellular responses to environmental changes occur on different levels. We investigated the translational response of yeast cells after mild hyperosmotic shock by isolating mRNA associated with multiple ribosomes (polysomes) followed by array analysis. Globally, recruitment of preexisting mRNAs to ribosomes (translational response) is faster than the transcriptional response.

Short-term glucocorticoid treatment increases insulin secretion in islets derived from lean mice through multiple pathways and mechanisms.

Chronic exposure to elevated levels of glucocorticoids leads to metabolic dysfunctions with hyperglycemia and insulin resistance. Long-term treatment with glucocorticoids induces severe impairment of glucose-stimulated insulin secretion. We analyzed the effects of short-, and medium-term (2-120h) treatment with 50-200nM glucocorticoids on primary pancreatic islet cultures derived from lean C57BL/6J mice.

The Bre5/Ubp3 ubiquitin protease complex from budding yeast contributes to the cellular response to DNA damage.

The ubiquitination status of proteins can control numerous aspects of protein function through targeted destruction or by altering protein-protein interactions, subcellular localization, or enzymatic activity. In addition to enzymes that mediate the conjugation of ubiquitin moieties to target proteins, there are enzymes that catalyze the removal of ubiquitin, termed ubiquitin proteases. One such ubiquitin protease, Ubp3, exists in a complex with a partner protein: Bre5.

Active site variability of type 1 11beta-hydroxysteroid dehydrogenase revealed by selective inhibitors and cross-species comparisons.

The NADPH-dependent enzyme type 1 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) activates in a tissue-specific manner circulating pro-glucocorticoid hormones (cortisone in humans) to the 11beta-OH ligand (cortisol in humans), which is able to bind to its cognate receptor and regulate gene transcription. Modulation of this pre-receptor activation mechanism by selective enzyme inhibitors is a desirable goal in the treatment of insulin resistance and related metabolic disorders. Like most other hydroxysteroid dehydrogenases 11beta-HSD1 belongs to the evolutionarily conserved enzyme superfamily of short-chain dehydrogenases/reductases (SDR).

Short-chain dehydrogenases/reductases (SDR): the 2002 update.

Short-chain dehydrogenases/reductases (SDR) form a large, functionally heterogeneous protein family presently with about 3000 primary and about 30 3D structures deposited in databases. Despite low sequence identities between different forms (about 15-30%), the 3D structures display highly similar alpha/beta folding patterns with a central beta-sheet, typical of the Rossmann-fold. Based on distinct sequence motifs functional assignments and classifications are possible, making it possible to build a general nomenclature system.