Ubiquitin and ubiquitin conjugates in human lens

Jahngen-Hodge, Jessica; Cyr, Deanna E.; Laxman, Eric; Taylor, Allen

doi:10.1016/0014-4835(92)90016-l

Cited by 62 publications

(37 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3C showed that more substrates are available for ubiquitinylation in the cells upon oxidative stress and recovery. This hypothesis is consistent with a recent study that showed that the ability of old lenses to mount a ubiquitinylation response to oxidative stress decreased coincidentally with the accumulation of damaged proteins (35,65,66). In addition to degradation of damaged proteins, the ubiquitin-dependent pathway is also involved in controlling the levels of several key regulatory proteins, such as IB (27,67,68) and p53 (31, 32, 69 -71).…”

Section: Discussionsupporting

confidence: 79%

Activity of Ubiquitin-dependent Pathway in Response to Oxidative Stress

Shang

Gong

Taylor

1997

Journal of Biological Chemistry

Self Cite

213

134

View full text Add to dashboard Cite

Relations between the ubiquitin pathway and cellular stress have been noted, but data regarding responses of the ubiquitin pathway to oxidative stress are scanty. This paper documents the response of this pathway to oxidative stress in lens cells. A brief exposure of lens epithelial cells to physiologically relevant levels of H 2 O 2 induces a transient increase in activity of the ubiquitindependent pathway. Ubiquitin conjugation activity was maximal and increased 3.5-9.2-fold over the activity noted in untreated cells by 4 h after removal of H 2 O 2 . By 24 h after removal of H 2 O 2 , ubiquitin conjugation activity returned to the level noted in untreated cells. In parallel to the changes in ubiquitin conjugation activity, the activity of ubiquitin-activating enzyme (E1), as determined by thiol ester formation, increased 2-6.7-fold during recovery from oxidation. Addition of exogenous E1 resulted in an increase in ubiquitin conjugation activity and in the levels of ubiquitin carrier protein (E2)-ubiquitin thiol esters in both the untreated cells and the H 2 O 2 -treated cells. These data suggest that E1 is the rate-limiting enzyme in the ubiquitin conjugation process and that the increases in ubiquitin conjugation activity which are induced upon recovery from oxidation are primarily due to increased E1 activity. The oxidation-and recovery-induced up-regulation of E1 activity is primarily due to post-synthetic events. Substrate availability and up-regulation of E2 activities also appear to be related to the enhancement in ubiquitinylation upon recovery from oxidative stress. The oxidationinduced increases in ubiquitin conjugation activity were associated with an increase in intracellular proteolysis, suggesting that the transient increase in ubiquitinylation noted upon recovery from oxidative stress may play a role in removal of damaged proteins from the cells.

show abstract

Section: Discussionsupporting

confidence: 79%

Activity of Ubiquitin-dependent Pathway in Response to Oxidative Stress

Shang

Gong

Taylor

1997

Journal of Biological Chemistry

Self Cite

213

134

View full text Add to dashboard Cite

show abstract

“…This might explain why ubiquitin conjugates are accumulated in response to oxidative stress and upon aging (3,37,50,(55)(56)(57)(58). Accumulation of ubiquitin conjugates in the brain is a characteristic of age-related diseases such as Alzheimer and Parkinson and cataracts (59,60). Further studies regarding relationships between Lys 6 modification and accumulation of ubiquitin per se or ubiquitin conjugates will reveal new roles for ubiquitin in health and disease.…”

mentioning

confidence: 99%

Lys6-modified Ubiquitin Inhibits Ubiquitin-dependent Protein Degradation

Shang

Deng

Liu

et al. 2005

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Ubiquitin plays essential roles in various cellular processes; therefore, it is of keen interest to study the structure-function relationship of ubiquitin itself. We investigated the modification of Lys 6 of ubiquitin and its physiological consequences. Mass spectrometry-based peptide mapping and N-terminal sequencing demonstrated that, of the 7 Lys residues in ubiquitin, Lys 6 was the most readily labeled with sulfosuccinimidobiotin. Lys 6 -biotinylated ubiquitin was incorporated into high molecular mass ubiquitin conjugates as efficiently as unmodified ubiquitin. However, Lys 6 -biotinylated ubiquitin inhibited ubiquitin-dependent proteolysis, as conjugates formed with Lys 6 -biotinylated ubiquitin were resistant to proteasomal degradation. Ubiquitins with a mutation of Lys 6 had similar phenotypes as Lys 6 -biotinylated ubiquitin. Lys 6 mutant ubiquitins (K6A, K6R, and K6W) also inhibited ATP-dependent proteolysis and caused accumulation of ubiquitin conjugates. Conjugates formed with K6W mutant ubiquitin were also resistant to proteasomal degradation. The dominant-negative effect of Lys 6 -modified ubiquitin was further demonstrated in intact cells. Overexpression of K6W mutant ubiquitin resulted in accumulation of intracellular ubiquitin conjugates, stabilization of typical substrates for ubiquitin-dependent proteolysis, and enhanced susceptibility to oxidative stress. Taken together, these results show that Lys 6 -modified ubiquitin is a potent and specific inhibitor of ubiquitin-mediated protein degradation.

show abstract

“…These systems achieve a stable redox environment [3 -5]. The lens also possesses systems for the repair or removal of damaged proteins [6] and nucleic acids [7].…”

mentioning

confidence: 99%

The ageing lens and cataract: a model of normal and pathological ageing

Michael

Bron

2011

Phil. Trans. R. Soc. B

367

277

View full text Add to dashboard Cite

Cataract is a visible opacity in the lens substance, which, when located on the visual axis, leads to visual loss. Age-related cataract is a cause of blindness on a global scale involving genetic and environmental influences. With ageing, lens proteins undergo non-enzymatic, post-translational modification and the accumulation of fluorescent chromophores, increasing susceptibility to oxidation and cross-linking and increased light-scatter. Because the human lens grows throughout life, the lens core is exposed for a longer period to such influences and the risk of oxidative damage increases in the fourth decade when a barrier to the transport of glutathione forms around the lens nucleus. Consequently, as the lens ages, its transparency falls and the nucleus becomes more rigid, resisting the change in shape necessary for accommodation. This is the basis of presbyopia. In some individuals, the steady accumulation of chromophores and complex, insoluble crystallin aggregates in the lens nucleus leads to the formation of a brown nuclear cataract. The process is homogeneous and the affected lens fibres retain their gross morphology. Cortical opacities are due to changes in membrane permeability and enzyme function and shear-stress damage to lens fibres with continued accommodative effort. Unlike nuclear cataract, progression is intermittent, stepwise and non-uniform.

show abstract

Ubiquitin and ubiquitin conjugates in human lens

Cited by 62 publications

References 16 publications

Activity of Ubiquitin-dependent Pathway in Response to Oxidative Stress

Activity of Ubiquitin-dependent Pathway in Response to Oxidative Stress

Lys6-modified Ubiquitin Inhibits Ubiquitin-dependent Protein Degradation

The ageing lens and cataract: a model of normal and pathological ageing

Contact Info

Product

Resources

About