Age-Related Decline of Rat Liver Multicatalytic Proteinase Activity and Protection from Oxidative Inactivation by Heat-Shock Protein 90

Conconi, Mariangela; Szweda, Luke I.; Levine, Rodney L.; Stadtman, Earl R.; Friguet, Bertrand

doi:10.1006/abbi.1996.0303

Cited by 212 publications

(121 citation statements)

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“…While earlier studies employing fibroblasts have suggested that the 20S proteasome might be resistant to ageassociated or oxidative stress-induced modifications [18,42] recent studies employing cardiac muscles and liver from aged rodent cohorts, demonstrate significant decline in 20S proteasomal activities [21,43]. Our current results with 20S proteasomes preparations which demonstrate chymotrypsin-like activity to be most sensitive to age-related modifications is in line with our previously reported observation obtained with 26S proteasomes, as well as, data reported by Carrard et al, employing peripheral blood lymphocytes from human subjects [4,22].…”

Section: Discussionmentioning

confidence: 99%

Redox regulation of the proteasome in T lymphocytes during aging

Das

Ponnappan

2007

Free Radical Biology and Medicine

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Proteasome is a major cellular organelle responsible for the regulated turn-over of both normal and misfolded proteins. Recent reports from our laboratory have implicated lowered proteasomal chymotryptic activity to be responsible for decreased induction of the transcription factor NFκB in T lymphocytes during aging. In this study, we have further analyzed the basis for this decline in proteasomal function, by focusing on the role of oxidative stress. Upon exposure to the pro-oxidant BSO, both ATP-stimulatable 26S, as well as ATP-independent 20S proteasomal catalytic activity could be down-regulated in T cells from young donors, mimicking the decline observed in T cells from the elderly. Loss in these catalytic activities, following exposure to pro-oxidant stimulus also resulted in a decline in both activation-induced proliferation as well as degradation of the inhibitor IκBα, with concomitant increase in the accumulation of carbonylated proteins, mimicking responses seen in T cells from the elderly. Pretreatment with an antioxidant, NAC could override pro-oxidantmediated, but not age-associated decrease in both 20S proteasomal activities. These results suggest that the decrease in proteasomal activities observed during aging may be secondary to oxidative stress and underlie immune senescence.

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Section: Discussionmentioning

confidence: 99%

Redox regulation of the proteasome in T lymphocytes during aging

Das

Ponnappan

2007

Free Radical Biology and Medicine

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“…Purification of 20 S Proteasome-The 20 S proteasome was purified from frozen livers of 4 -6-month-old Fischer 344 rats essentially as described previously (26). The final purified proteasome was made to a concentration of approximately 1 mg/ml in 50 mM potassium phosphate (pH 7.0), 0.1 M KCl and stored at Ϫ70°C.…”

Section: Methodsmentioning

confidence: 99%

Selective Degradation of Oxidized Calmodulin by the 20 S Proteasome

Ferrington

Sun

Murray

et al. 2001

Journal of Biological Chemistry

115

184

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We have investigated the mechanisms that target oxidized calmodulin for degradation by the proteasome. After methionine oxidation within calmodulin, rates of degradation by the 20 S proteasome are substantially enhanced. Mass spectrometry was used to identify the time course of the proteolytic fragments released from the proteasome. Oxidized calmodulin is initially degraded into large proteolytic fragments that are released from the proteasome and subsequently degraded into small peptides that vary in size from 6 to 12 amino acids. To investigate the molecular determinants that result in the selective degradation of oxidized calmodulin, we used circular dichroism and fluorescence spectroscopy to assess oxidant-induced structural changes. There is a linear correlation between decreases in secondary structure and the rate of degradation. Calcium binding or the repair of oxidized calmodulin by methionine sulfoxide reductase induces comparable changes in ␣-helical content and rates of degradation. In contrast, alterations in the surface hydrophobicity of oxidized calmodulin do not alter the rate of degradation by the proteasome, indicating that changes in surface hydrophobicity do not necessarily lead to enhanced proteolytic susceptibility. These results suggest that decreases in secondary structure expose proteolytically sensitive sites in oxidized calmodulin that are cleaved by the proteasome in a nonprocessive manner.Critical to the ability of a cell to reestablish cellular homeostasis after a range of different environmental stresses is the removal of oxidatively modified proteins by the proteasome (1, 2). The proteasome represents approximately 1% of the total cellular protein and is present in the cytosol and nuclei of all mammalian cells in two major forms (i.e. the 20 S and 26 S proteasomes) (3). The 20 S proteasome is a 700-kDa complex with a 10 -20-Å-diameter opening into an internal cavity that provides a sequestered environment for proteolysis. The 26 S proteasome is a 2000-kDa complex containing two 19 S regulatory complexes bound to the 20 S multicatalytic core. The 26 S proteasome is responsible for the degradation of the majority of cellular proteins through an ATP-dependent and ubiquitinmediated pathway (4 -6). In contrast, the 20 S proteasome core selectively degrades a range of different oxidized proteins in an ATP-independent manner and has been suggested to represent the primary mechanism in the rapid removal of oxidized proteins after oxidative stress (7-11). The signal for recognition and degradation of oxidized proteins by the 20 S proteasome is unknown but has been suggested to involve (i) exposure of hydrophobic surfaces after oxidative modification, (ii) recognition of molecular "markers" associated with the oxidative modification of specific amino acid side chains, and (iii) increases in the conformational flexibility of oxidized proteins (12-16).To distinguish which signals are involved in targeting an oxidized protein for degradation by the 20 S proteasome, we have investigated the mech...

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“…As mentioned, FOXOs are involved in the proteasome system degradation of short‐lived and regulatory cytosolic proteins. Aging is associated with a decreased proteasomal activity, leading to excess of damaged proteins in muscle, liver, and heart (Conconi et al ., 1996; Petropoulos et al ., 2000; Bulteau et al ., 2002; Husom et al ., 2004). Moreover, pathogenesis of neurodegenerative disorders such as Parkinson's, Alzheimer's, or Huntington's disease is generally related to an abnormal ubiquitin‐proteasome mechanism as either a primary cause or secondary consequence (Ciechanover & Brundin, 2003; Kikis et al ., 2010; Webb & Brunet, 2014).…”

Section: Foxo and Autophagymentioning

confidence: 99%

“…Aging is associated with a decreased proteasomal activity, leading to excess of damaged proteins in muscle, liver, and heart (Conconi et al ., 1996; Petropoulos et al ., 2000; Bulteau et al ., 2002; Husom et al ., 2004). Foxo3 has been shown to be a transcriptional regulator of muscle‐specific E3 ubiquitin ligases, which are major effectors of protein degradation in muscle (Sandri et al ., 2004, 2006; Stitt et al ., 2004).…”

Section: Animal Modelsmentioning

confidence: 99%

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

2015

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SummaryAging constitutes the key risk factor for age‐related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which “protective genes” are carried by long‐lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin‐like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed.

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Age-Related Decline of Rat Liver Multicatalytic Proteinase Activity and Protection from Oxidative Inactivation by Heat-Shock Protein 90

Cited by 212 publications

References 0 publications

Redox regulation of the proteasome in T lymphocytes during aging

Redox regulation of the proteasome in T lymphocytes during aging

Selective Degradation of Oxidized Calmodulin by the 20 S Proteasome

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

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