Targeting the ubiquitin-proteasome degradation pathway has become a promising approach for cancer therapy. Previous studies have shown that proteasome inhibition leads to apoptosis in various cancer cells. The mechanism by which apoptosis occurs are not fully understood and can be cell type and/or inhibitor specific. In this study, we investigated the mechanism of mitochondrial activation by pr...

The consolidation of fear memories is known to depend on a number of critical cellular processes including de novo protein synthesis and 26S proteasome-dependent protein degradation following auditory fear conditioning (Jarome et al., 2011; Kwapis et al., 2011). Early work has suggested that protein degradation, mediated by the ubiquitin proteasome system (UPS), may regulate the requirement for...

Sepsis is one of the leading causes of acute kidney injury (AKI). Septic patients who develop acute kidney injury (AKI) are at increased risk of death. To date there is no effective treatment for AKI or septic AKI. Based on their anti-inflammatory properties, we examined the effects of nicotinic acetylcholine receptor agonists on renal damage using a mouse model of lipopolysaccharide (LPS)-indu...

PURPOSE Elevated metabolic activity of ovarian cancer cells causes increased ubiquitin-proteasome-system (UPS) stress, resulting in their greater sensitivity to the toxic effects of proteasomal inhibition. The proteasomes and a potentially compensatory histone deacetylase 6 (HDAC6)-dependent lysosomal pathway mediate eukaryotic protein turnover. We hypothesized that up-regulation of the HDAC6-d...

Sirtuin6(SIRT6) has been implicated as a key factor in aging and aging-related diseases. However, the role of SIRT6 in cellular senescence has not been fully understood. Here, we show that SIRT6 repressed the expression of p27Kip1 (p27) in cellular senescence. The expression of SIRT6 was reduced during cellular senescence, whereas enforced SIRT6 expression promoted cell proliferation and antago...

BACKGROUND Multiple myeloma (MM) is an incurable malignancy that is diagnosed in approximately 15,000 people in the United States each year. The novel proteasome inhibitor bortezomib has shown antitumor activity in preclinical studies and has entered clinical trials, with encouraging results to date. METHODS We review and summarize preclinical work demonstrating the tumoricidal effects of pro...

Proteasome inhibitors have been suggested as potential anticancer agents in many clinical trials. Recent evidence indicates that proteasomal deubiquitinase (DUB) inhibitors, bearing a differentmechanism from that of traditional proteasome inhibitors, would be appropriate candidates for new anticancer drug development. In the present study, we describe the deubiquitinase inhibition of 19S regula...

The Plasmodium proteasome has been suggested to be a potential antimalarial drug target; however, toxicity of inhibitors has prevented validation of this enzyme in vivo. We report a screen of a library of 670 analogs of the recent US Food and Drug Administration-approved inhibitor, carfilzomib, to identify compounds that selectively kill parasites. We identified one compound, PR3, that has sign...

In patients with Huntington's disease (HD), the proteolytic activity of the ubiquitin proteasome system (UPS) is reduced in the brain and other tissues. The pathological hallmark of HD is the intraneuronal nuclear protein aggregates of mutant huntingtin. We determined how to enhance UPS function and influence catalytic protein degradation and cell survival in HD. Proteasome activators involved ...

We have recently shown that IKK complex plays an important non-genomic role in platelet function, i.e., regulates SNARE machinery-dependent membrane fusion. In this connection, it is well known that MALT1, whose activity is modulated by proteasome, plays an important role in the regulation of IKK complex. Therefore, the present studies investigated the mechanism by which IKK signaling is regula...