Proteasome inhibitors induce heat shock response and increase IL-6 expression in human intestinal epithelial cells

Pritts, Timothy A.; Hungness, Eric S.; Hershko, Dan; Robb, Bruce W.; Sun, Xiaoyan; Luo, Guangju; Fischer, Josef E.; Wong, Hector R.; Hasselgren, Per Olof

doi:10.1152/ajpregu.00492.2001

Cited by 52 publications

(58 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…the power stroke model of protein translocation, do not lead to better agreement with the experiment than the Brownian ratchet model [11]. Noteworthy, in these ratchet effects transport is possible only in a certain temperature interval, and stochasticity, intrinsically present due to fluctuations in any biochemical reaction [15,16], provides the driving mechanism.Here we propose a model for active protein translocation in the proteasome to explain the peptide size dependence of the transport velocity as well as its temperature dependence which possibly explains the mechanism of temperature reaction or heat shock response, regulating the proteasome activity in the case of some diseases [17,18,19,20]. The results describe a system size ratchet effect that is related to similar effects which have been described recently for other noise-induced phenomena [21].…”

supporting

confidence: 69%

Peptide-size–dependent active transport in the proteasome

Zaikin

Pöschel

2005

Europhys. Lett.

View full text Add to dashboard Cite

We investigate the transport of proteins inside the proteasome and propose an active transport mechanism based on a spatially asymmetric interaction potential of peptide chains. The transport is driven by fluctuations which are always present in such systems. We compute the peptide-size dependent transport rate which is essential for the functioning of the proteasome. In agreement with recent experiments, varying temperature changes the transport mechanism qualitatively. [4,5,6] and to predict the cleavage results [7], however, basic principles of the proteasome operation mechanisms are still poorly understood, mainly due to the lack of experimental results.In this Letter, we focus on understanding of protein translocation inside the proteasome, leaving the mechanisms of cleavage, targeting, etc. beyond the scope. The main question is: given proteasomes are highly complex pipe-like structures of tenthousands atoms of almost perfect left-right symmetry with respect to the axis of the pipe [9], thus, operating bi-directional. To be cleaved, a protein has to enter the proteasome at one side, pass the active sites (where the cleavage occurs), which makes about 1/3 of the total length of the pipe. Then the cleaved peptides have to pass all the way through the pipe to finally reappear at the other side of the proteasome. Although there is a number of examples where protein transport in cells occurs due to diffusion, i.e. Brownian motion [8], diffusive transport may be excluded as the main mechanism for translocation in the proteasome because of the enormous cargo [10]. Also other proposed transport mechanisms, such as the power stroke model of protein translocation do not suffice to explain translocation [11]. Therefore, the question arises how the protein's motion inside the proteasome is driven?Since proteasomes are large multi-subunit structures consisting of proteins, the mechanism of the protein transport is directly related to protein-protein interaction. In [12] it has been noticed that if attachment and detachment rates are specified asymmetrically, the protein-protein binding interaction acts as a ratchet. Following this argumentation, active protein transport, based on the mechanism of a molecular ratchet, has been studied for transport through membranes [13] and has been also discussed as a mechanism for cytosolic destruction by the proteasome [14]. Moreover, maximum likelihood tests have shown that other models, e.g. the power stroke model of protein translocation, do not lead to better agreement with the experiment than the Brownian ratchet model [11]. Noteworthy, in these ratchet effects transport is possible only in a certain temperature interval, and stochasticity, intrinsically present due to fluctuations in any biochemical reaction [15,16], provides the driving mechanism.Here we propose a model for active protein translocation in the proteasome to explain the peptide size dependence of the transport velocity as well as its temperature dependence which possibly explains the mechanism of temperature r...

show abstract

supporting

confidence: 69%

Peptide-size–dependent active transport in the proteasome

Zaikin

Pöschel

2005

Europhys. Lett.

View full text Add to dashboard Cite

show abstract

“…Hsp72, another cytoprotective heat-shock protein, is reported to be upregulated by exposure to MG132 (86). In line with this concept, another small heat-shock protein, hsp27, has been implicated in bortezomib resistance in lymphoma (13).…”

Section: Fig 4 Alternate Explanation For Antioxidant Protection Of mentioning

confidence: 90%

Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

Chandra

2009

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

The past decade has seen an exponential increase in the number of cancer therapies with defined molecular targets. Interestingly, many of these new agents are also documented to raise levels of intracellular reactive oxygen species (ROS) in addition to inhibiting a biochemical target. In most cases, the exact link between the primary target of the drug and effects on cellular redox status is unknown. However, it is important to understand the role of oxidative stress in promoting cytotoxicity by these agents, because the design of multiregimen strategies could conceivably build on these redox alterations. Also, drug resistance mediated by antioxidant defenses could potentially be anticipated and circumvented with improved knowledge of the redoxrelated effects of these targeted agents. Given the large number of targeted chemotherapies, in this review, we focus on selected agents that have shown promise in hematologic malignancies: proteasome inhibitors, histone deacetylase inhibitors, Bcl-2-targeted agents, and a kinase inhibitor called adaphostin. Despite structural differences within classes of these compounds, a commonality of causing increased oxidative stress exists, which contributes to induction of cell death. Antioxid. Redox Signal. 11, 1123-1137.

show abstract

“…A potential limitation of the protocols used in this study to inhibit HSP70 expression by T. gondii (i.e., the combination of transient transfection with antisense oligonucleotides and quercetin) is that quercetin and other related flavonoids are known to induce multiple changes in the cells exposed to them (32)(33)(34)(35). The complex nature of the relationship between flavonoid compounds such as quercetin, heat shock proteins, and the immune response obviously requires further characterization, but it should be emphasized that, in this study, only parasites were treated with quercetin; the host cells that were used to examine the effects of parasite HSP70 on various parameters of the immune response were not exposed directly to quercetin at any time.…”

Section: Discussionmentioning

confidence: 99%