Proteasome‐dependent degradation of oxidized proteins in MRC‐5 fibroblasts

Sitte, Nicolle; Merker, Katrin; Grune, Tilman

doi:10.1016/s0014-5793(98)01495-1

Cited by 172 publications

(111 citation statements)

References 22 publications

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“…Experimental investigations to determine the degradation rate of oxidized proteins in mammalian cells have been performed by our group (17,41,(104)(105)(106)(107)(108) and by others (109)(110)(111)(112)(113), by applying external stress using different oxidative agents, including H 2 O 2 , ONOO 2 , SIN-1, and paraquat. In all these cases it was demonstrated that inhibition or removal of proteasomes resulted in a loss of the ability of cells to degrade oxidized proteins (114,115).…”

Section: The Degradation Of Oxidized Proteins-a Function Of the 20s Pmentioning

confidence: 99%

The proteasome and its role in the degradation of oxidized proteins

2008

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SummaryThe generation of free radicals and the resulting oxidative modification of cell structures are omnipresent in mammalian cells. This includes the permanent oxidation of proteins leading to the disruption of the protein structure and an impaired functionality. In consequence, these oxidized proteins have to be removed in order to prevent serious metabolic disturbances. The most important cellular proteolytic system responsible for the removal of oxidized proteins is the proteasomal system. For normal functioning, the proteasomal system needs the coordinated interaction of numerous components. This review describes the fundamental functions of the 20S ''core'' proteasome, its regulators, and the roles of the proteasomal system beyond the removal of oxidized proteins in mammalian cells. IUBMBIUBMB Life, 60(11): 743-752, 2008

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Section: The Degradation Of Oxidized Proteins-a Function Of the 20s Pmentioning

confidence: 99%

The proteasome and its role in the degradation of oxidized proteins

2008

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“…14 Protein carbonylation can modify the rate of protein degradation, with some proteins showing increased and others reduced turnover. 8,[15][16][17][18][19][20] Perhaps most significantly, carbonylation of a protein can also reduce its activity, 21 for example glutamine synthase exposed to metal catalysed oxidation has reduced enzyme activity. 22 Consequently, cells that have large numbers of protein carbonyls may be expected to have impaired function.…”

Section: Introductionmentioning

confidence: 99%

Carbonylation of glycolytic proteins is a key response to drug-induced oxidative stress and apoptosis

2003

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Recent work has highlighted the importance of protein posttranslational modifications such as phosphorylation (enzymatic) and nitrosylation (nonenzymatic) in the early stages of apoptosis. In this study, we have investigated the levels of protein carbonylation, a nonenzymatic protein modification that occurs in conditions of cellular oxidative stress, during etopside-induced apoptosis of HL60 cells. Within 1 h of VP16 treatment, a number of proteins underwent carbonylation due to oxidative stress. This was inhibited by the antioxidant N-acetyl-L-cysteine. Among the proteins found to be carbonylated were glycolytic enzymes. Subsequently, we found that the rate of glycolysis was significantly reduced, probably due to a carbonylation mediated reduction in enzymatic activity of glycolytic enzymes. Our work demonstrates that protein carbonylation can be rapidly induced through cytotoxic drug treatment and may specifically inhibit the glycolytic pathway. Given the importance of glycolysis as a source of cellular ATP, this has severe implications for cell function.

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“…In cell-free systems, accumulation of these alterations renders proteins susceptible to degradation [23,24]. Exposure of cells to moderate levels of H 2 O 2 increases intracellular proteolysis rates [25,26], and a selective increase in degradation of oxidized proteins in erythrocytes, fibroblasts or macrophages after H 2 O 2 treatment has been demonstrated [27][28][29]. As the cell's major multicatalytic protease complex, the proteasome plays an important role in removal of oxidized proteins as shown in e.g.…”

Section: Introductionmentioning

confidence: 99%

“…As the cell's major multicatalytic protease complex, the proteasome plays an important role in removal of oxidized proteins as shown in e.g. fibroblasts, liver epithelial cell lines and hematopoietic cell lines [25,26,28], although other proteases are also implicated [30,31]. Interestingly, the levels of oxidants used in these in vitro systems are close to the ones existing in tumors or in the synovial fluid of RA patients.…”

Section: Introductionmentioning

confidence: 99%

Oxidative‐stress‐induced T lymphocyte hyporesponsiveness is caused by structural modification rather than proteasomal degradation of crucial TCR signaling molecules

2003

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In several human pathologies (e.g. cancer, rheumatoid arthritis, AIDS and leprosy) oxidative stress induces T cell hyporesponsiveness. Hyporesponsive T cells often appear to display impaired expression of some (e.g. TCR-´, p56 lck and LAT) but not all (e.g. TCR- § g and CD3-4 ) crucial TCR-proximal signaling molecules but the underlying mechanisms have as yet not been identified. Using an in vitro system for oxidative-stress-induced T cell hyporesponsiveness we here report two sequential effects of oxidative stress on TCR signaling molecules: protein alterations and proteasomal degradation. We have identified the C-terminal part of TCR-´and the membrane-proximal domain of p56 lck as potential targets for modifications induced by reactive oxygen species. Oxidative-stress-exposed proteins were differentially susceptible to proteasomal degradation: whereas modified TCR-´was relatively resistant, reactive oxygen species (ROS)-altered LAT and p56 lck were much more susceptible. Importantly, we found that T cell hyporesponsiveness best correlated with ROS-dependent protein alteration since inhibition of proteasomal degradation did not restore function. Finally, our data provide an explanation for the paradox of reduced TCR-´signals combined with unaltered TCR- § g and CD3-4 expression levels: the TCR-´chain in hyporesponsive T cells is still expressed but no longer detectable by certain mAb recognizing ROS-sensitive epitopes.

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Proteasome‐dependent degradation of oxidized proteins in MRC‐5 fibroblasts

Cited by 172 publications

References 22 publications

The proteasome and its role in the degradation of oxidized proteins

The proteasome and its role in the degradation of oxidized proteins

Carbonylation of glycolytic proteins is a key response to drug-induced oxidative stress and apoptosis

Oxidative‐stress‐induced T lymphocyte hyporesponsiveness is caused by structural modification rather than proteasomal degradation of crucial TCR signaling molecules

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