Endotoxic shock is a serious systemic inflammatory response to an external biological stressor. The responsiveness of NF-kappaB is built upon rapid protein modification and degradation involving the ubiquitin proteasome pathway. Using transgenic mice, we have obtained in vivo evidence that interference with this pathway can alleviate the symptoms of toxic shock. We posit that administration of ...

With this motivation, the groups of Michael Groll at the Technical University of Munich and of Marcus Groettrup at the University of Konstanz have recently solved the crystal structures of both the constitutive proteasome and the immunoproteasome of mice, each with and without the epoxyketone PR957, which is the only selective inhibitor of b5i known so far. In addition, the researchers also sol...

Accumulating evidence has implicated the proteasome in the processing of proteins along the major histocompatibility complex (MHC) class I presentation pathway. The availability of potent proteasome inhibitors provides an opportunity to examine the role ofproteasome function in antigen presentation by MHC class I molecules to CD8 + cytotoxic T lymphocytes (CTLs). We have investigated the proces...

In this work we present evidence that A769662, a novel activator of AMP-activated protein kinase (AMPK), is able to inhibit the function of the 26S proteasome by an AMPK-independent mechanism. Contrary to the mechanism of action of most proteasome inhibitors, A769662 does not affect the proteolytic activities of the 20S core subunit, defining in this way a novel mechanism of inhibition of 26S p...

Emerging evidence suggests that dysfunction of the ubiquitin-proteasome system is involved in the pathogenesis of numerous senile degenerative diseases including retinal disorders. The aim of this study was to assess whether there is a link between proteasome regulation and retinal pigment epithelium (RPE)-mediated expression of extracellular matrix genes. For this purpose, human retinal pigmen...

Proteasome inhibition forms the cornerstone of antimyeloma therapy. The first-in-class proteasome inhibitor, bortezomib, either alone or in combination with other chemotherapeutic agents, induces high overall response rates and response qualities in patients with clinically and molecularly defined high-risk disease. However, resistance to bortezomib and neurotoxicity associated with the treatme...

AIMS Increased levels of reactive oxygen species cause oxidative stress and severely damage lipids, proteins, and DNA. We have previously shown that partial proteasome inhibition induces an antioxidative gene pattern in endothelial cells. Here, we elucidate the mechanisms of proteasome inhibitor-mediated upregulation of antioxidative enzymes and cytoprotection. METHODS AND RESULTS Non-toxic p...

Activation of certain phosphoinositidase-C-linked cell-surface receptors is known to cause an acceleration of the proteolysis of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptors and, thus, lead to Ins(1,4,5)P3-receptor down-regulation. In the current study we have sought to determine whether the ubiquitin/proteasome pathway is involved in this adaptive response. The data presented show (i)...