Ubiquitin- and proteasome-dependent pathway of protein degradation as an emerging therapeutic target

Wójcik, Cezary

doi:10.1517/14728222.4.1.89

Cited by 9 publications

(7 citation statements)

References 191 publications

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“…Although the data presented here show some promise for the use of proteasome inhibitors in skeletal muscle-wasting syndromes, an obstacle facing proteasome inhibition is the ubiquitous expression of proteasomes and the possibility of unacceptable toxicity. Although the ubiquitin-proteasome pathway has a general function in intracellular protein turnover, it also plays a key role in many biological processes, such as MHC class 1 antigen presentation, cell division, and NF-KB activation (7,9,11,12). Selectivity and a lack of toxicity are particularly critical for many elderly patients who may have some degree of muscle atrophy but are otherwise healthy.…”

Section: Discussionmentioning

confidence: 99%

“…An imbalance such that proteolysis prevails over synthesis is associated with skeletal muscle atrophy, For instance, a decrease in circulating growth hormone or androgen levels as a consequence of aging causes a decreased rate of protein synthesis that leads to skeletal muscle wasting or sarcopenia (1,2). When the rate of protein degradation exceeds that of protein synthesis as a consequence of disease states, such as cancer cachexia, renal failure, sepsis, and skeletal muscle denervation, skeletal muscle atrophy ensues (3)(4)(5)(6)(7). Although sarcopenia of aging and other forms of muscle wasting are important clinically, there are few therapeutic options for the treatment of any form of skeletal muscle atrophy.…”

Section: Introductionmentioning

confidence: 99%

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Reduction of Skeletal Muscle Atrophy by a Proteasome Inhibitor in a Rat Model of Denervation

Beehler

Sleph

Benmassaoud

et al. 2006

Exp Biol Med (Maywood)

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The ubiquitin-proteasome system is the primary proteolytic pathway implicated in skeletal muscle atrophy under catabolic conditions. Although several studies showed that proteasome inhibitors reduced proteolysis under catabolic conditions, few studies have demonstrated the ability of these inhibitors to preserve skeletal muscle mass and architecture in vivo. To explore this, we studied the effect of the proteasome inhibitor Velcade (also known as PS-341 and bortezomib) in denervated skeletal muscle in rats. Rats were given vehicle or Velcade (3 mg/kg po) daily for 7 days beginning immediately after induction of muscle atrophy by crushing the sciatic nerve. At the end of the study, the rats were euthanized and the soleus and extensor digitorum longus (EDL) muscles were harvested. In vehicle-treated rats, denervation caused a 33.5 +/- 2.8% and 16.2 +/- 2.7% decrease in the soleus and EDL muscle wet weights (% atrophy), respectively, compared to muscles from the contralateral (innervated) limb. Velcade significantly reduced denervation-induced atrophy to 17.1 +/- 3.3% in the soleus (P < 0.01), a 51.6% reduction in atrophy associated with denervation, with little effect on the EDL (9.8 +/- 3.2% atrophy). Histology showed a preservation of muscle mass and preservation of normal cellular architecture after Velcade treatment. Ubiquitin mRNA levels in denervated soleus muscle at the end of the study were significantly elevated 120 +/- 25% above sham control levels and were reduced to control levels by Velcade. In contrast, testosterone proprionate (3 mg/kg sc) did not alleviate denervation-induced skeletal muscle atrophy but did prevent castration-induced levator ani atrophy, while Velcade was without effect. These results show that proteasome inhibition attenuates denervation-induced muscle atrophy in vivo in soleus muscles. However, this mechanism may not be operative in all types of atrophy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Reduction of Skeletal Muscle Atrophy by a Proteasome Inhibitor in a Rat Model of Denervation

Beehler

Sleph

Benmassaoud

et al. 2006

Exp Biol Med (Maywood)

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“…This makes proteasome inhibitors very promising agents in cancer therapy, and they are already used in clinical trials [189,57]. The ability of proteasome inhibitors to induce apoptosis in certain cell types can be also exploited in the treatment of other pathological conditions [50] [190]. They also have potential to be used as immunosupressant drugs possibly useful in organ transplantation recipients [191].…”

Section: Discussionmentioning

confidence: 99%

Regulation of apoptosis by the ubiquitin and proteasome pathway

Wójcik

2002

J Cellular Molecular Medi

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108

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Regulated proteolysis plays important roles in cell physiology as well as in pathological conditions. In most of the cases, regulated proteolysis is carried out by the ubiquitin-and proteasome-dependent proteolytic system, which is also in charge of the bulk of cytoplasmic proteolysis. However, apoptosis or the process of programmed cell death is regulated by a different proteolytic system, i.e. by caspases, a family of specialized cysteine proteases. Nevertheless, there is plenty of evidence of a crosstalk between the apoptotic pathways and the ubiquitin and proteasome system, whose function in apoptosis appears to be very complex. Proteasome inhibitors induce apoptosis in multiple cell types, while in other they are relatively harmless or even prevent apoptosis induced by other stimuli. Proteasomes degrade specific proteins during apoptosis, but on the other hand some components of the proteasome system are degraded by caspases. The knowledge about the involvement of the ubiquitin-and proteasome-dependent system in apoptosis is already clinically exploited, since proteasome inhibitors are being tested as experimental drugs in the treatment of cancer and other pathological conditions, where manipulation of apoptosis is desirable.

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“…These are described in greater detail in recent reviews. 41,42 In this context, it is important to point out the types of assays used to determine whether alterations have occurred in the ubiqui-tin± proteasome pathway in either normal or pathological states. In most cases, if sufficient tissue is available, measurement of proteasome peptidase activity is the most definitive way of determining these changes.…”

Section: The Ubiquitin± Proteasome System In Pathological Conditionsmentioning

confidence: 99%

“…The elucidation of this transcription mechanism has naturally led to the development of an assortment of proteasome inhibitors as anti-inflammatory agents, which prevent activation of NFkB. 41,97 In this regard it was found, quite unexpectedly, that acetaldehyde, ethanol's primary oxidation product, long regarded as the actual hepatotoxin, may actually prevent ethanol induced inflammation by blocking NFkB activation. Lindros et al treated ethanol-fed rats with the aldehyde dehydrogenase (ALDH) inhibitors disulfuram and benzcoprine.…”

Section: Ubiquitin± Proteasome Involvement In Alcohol-induced Inflammmentioning

confidence: 99%

The ubiquitin‐proteasome system and its role in ethanol‐induced disorders

Donohue

2002

Addiction Biology

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Some of the most fundamental yet important cellular activities such as cell division and gene expression are controlled by short-lived regulatory proteins. The levels of these proteins are controlled by their rates of degradation. Similarly, protein catabolism plays a crucial role in prolonging cellular life by destroying damaged proteins that are potentially cytotoxic. A major player in these catabolic reactions is the ubiquitin-proteasome system, a novel proteolytic system that has become the primary proteolytic pathway in eukaryotic cells. Ubiquitin-mediated proteolysis is now regarded as the major pathway by which most intracellular proteins are destroyed. Equally important, from a toxicological standpoint, is that the ubiquitin-proteasome system is also widely considered to be a cellular defense mechanism, since it is involved in the removal of damaged proteins generated by adduct formation and oxidative stress. This review describes the history and the components of the ubiquitin-proteasome system, its regulation and its role in pathological states, with the major emphasis on ethanol-induced organ injury. The available literature cited here deals mainly with the effects of ethanol consumption on the ubiquitin-proteasome pathway in the liver. However, since this proteolytic system is an essential pathway in all cells it is an attractive experimental model and therapeutic target in extrahepatic organs such as the brain and heart that are also affected by excessive alcohol consumption.

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Ubiquitin- and proteasome-dependent pathway of protein degradation as an emerging therapeutic target

Cited by 9 publications

References 191 publications

Reduction of Skeletal Muscle Atrophy by a Proteasome Inhibitor in a Rat Model of Denervation

Reduction of Skeletal Muscle Atrophy by a Proteasome Inhibitor in a Rat Model of Denervation

Regulation of apoptosis by the ubiquitin and proteasome pathway

The ubiquitin‐proteasome system and its role in ethanol‐induced disorders

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