20S proteasome mediated degradation of DHFR: implications in neurodegenerative disorders

Amici, Manila; Sagratini, Danila; Pettinari, Assuntina; Pucciarelli, Stefania; Angeletti, Mauro; Eleuteri, Anna Maria

doi:10.1016/j.abb.2003.12.014

Cited by 14 publications

(9 citation statements)

References 41 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our findings that YB‐1 undergoes a limited proteolysis by the 20S proteasome that occurs in ubiquitin‐ and ATP‐independent manner indicate a specific mechanism of YB‐1 targeting. Several other proteins including α‐synuclein, p21 Cip1 , p53 and p73 were reported to be degraded by the 20S proteasome without ubiquitylation and, in some cases, without ATP (Tofaris et al , 2001; Touitou et al , 2001; Amici et al , 2004; Asher et al , 2005). In contrast to YB‐1, however, the above proteins were completely degraded by the 20S proteasome.…”

Section: Discussionmentioning

confidence: 99%

Proteasome-mediated cleavage of the Y-box-binding protein 1 is linked to DNA-damage stress response

Sorokin

Selyutina

Skabkin

et al. 2005

EMBO J

142

160

View full text Add to dashboard Cite

YB-1 is a DNA/RNA-binding nucleocytoplasmic shuttling protein whose regulatory effect on many DNA-and RNAdependent events is determined by its localization in the cell. Distribution of YB-1 between the nucleus and the cytoplasm is known to be dependent on nuclear targeting and cytoplasmic retention signals located within the C-terminal portion of YB-1. Here, we report that YB-1 undergoes a specific proteolytic cleavage by the 20S proteasome, which splits off the C-terminal 105-amino-acidlong YB-1 fragment containing a cytoplasmic retention signal. Cleavage of YB-1 by the 20S proteasome in vitro appears to be ubiquitin-and ATP-independent, and is abolished by the association of YB-1 with messenger RNA. We also found that genotoxic stress triggers a proteasome-mediated cleavage of YB-1 in vivo and leads to accumulation of the truncated protein in nuclei of stressed cells. Endoproteolytic activity of the proteasome may therefore play an important role in regulating YB-1 functioning, especially under certain stress conditions.

show abstract

Section: Discussionmentioning

confidence: 99%

Proteasome-mediated cleavage of the Y-box-binding protein 1 is linked to DNA-damage stress response

Sorokin

Selyutina

Skabkin

et al. 2005

EMBO J

142

160

View full text Add to dashboard Cite

show abstract

“…However, several proteins are degraded within the cells in an ATP‐ and Ub‐independent manner [29]. There is evidence that the 20 S complex can directly degrade protein substrates such as casein, lysozyme, insulin β‐chain, histone H3, ornithine decarboxylase, dihydrofolate reductase and oxidatively damaged proteins [30–33].…”

Section: The Proteasomementioning

confidence: 99%

Natural polyphenols as proteasome modulators and their role as anti‐cancer compounds

et al. 2008

Self Cite

View full text Add to dashboard Cite

The purpose of this review is to discuss the effect of natural antioxidant compounds as modulators of the 20S proteasome, a multi‐enzymatic multi‐catalytic complex present in the cytoplasm and nucleus of eukaryotic cells and involved in several cellular activities such as cell‐cycle progression, proliferation and the degradation of oxidized and damaged proteins. From this perspective, proteasome inhibition is a promising approach to anticancer therapy and such natural antioxidant effectors can be considered as potential relevant adjuvants and pharmacological models in the study of new drugs.

show abstract

“…The protease responsible for cleavage remains elusive, although several enzymes have been proposed to cleave α Syn in vivo . The 20S proteasome is capable of degrading proteins in a ubiquitin- and ATP-independent manner (Amici et al 2004; Bennett et al 1999; David et al 2002; Di Noto et al 2005; Liu et al 2003; Shringarpure et al 2003; Tofaris et al 2001; Touitou et al 2001). Studies have suggested that 20S particles outnumber both 26S and free regulatory particles in vivo , suggesting an independent role for 20S (Brooks et al 2000; Tanahashi et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Accelerated formation of α-synuclein oligomers by concerted action of the 20S proteasome and familial Parkinson mutations

Lewis

Yaeger

DeMartino

et al. 2010

J Bioenerg Biomembr

View full text Add to dashboard Cite

A hallmark of Parkinson disease (PD) is the formation of intracellular protein inclusions called Lewy bodies that also contain mitochondria. α-Synuclein (αSyn) is a major protein component of Lewy bodies, where it is in an amyloid conformation and a significant fraction is truncated by poorly understood proteolytic events. Previously, we demonstrated that the 20S proteasome cleaves αSyn in vitro to produce fragments like those observed in Lewy bodies and that the fragments accelerate the formation of amyloid fibrils from full-length αSyn. Three point mutations in αSyn are associated with early-onset familial PD: A30P, E46K, and A53T. However, these mutations have very different effects on the amyloidogenicity and vesicle-binding activity of αSyn, suggesting neither of these processes directly correlate with neurodegeneration. Here, we evaluate the effect of the disease-associated mutations on the fragmentation, conformation, and association reactions of αSyn in the presence of the 20S proteasome and liposomes. The 20S proteasome produced the C-terminal fragments from both the mutant and wildtype αSyn. These truncations accelerated fibrillization of all α-synucleins, but again there was no clear correlation between the PD-associated mutations and amyloid formation in the presence of liposomes. Recent data suggests that cellular toxicity is caused by a soluble oligomeric species, which is a precursor to the amyloid form and is immunologically distinguishable from both soluble monomeric and amyloid forms of αSyn. Notably, the rate of formation of the soluble, presumptively cytotoxic oligomers correlated with the disease-associated mutations when both 20S proteasome and liposomes were present. Under these conditions, the wildtype protein was also cleaved and formed the oligomeric structures, albeit at a slower rate, suggesting that 20S-mediated truncation of αSyn may play a role in sporadic PD as well. Evaluation of the biochemical reactions of the PD-associated α-synuclein mutants in our in vitro system provides insight into the possible pathogenetic mechanism of both familial and sporadic PD.

show abstract

20S proteasome mediated degradation of DHFR: implications in neurodegenerative disorders

Cited by 14 publications

References 41 publications

Proteasome-mediated cleavage of the Y-box-binding protein 1 is linked to DNA-damage stress response

Proteasome-mediated cleavage of the Y-box-binding protein 1 is linked to DNA-damage stress response

Natural polyphenols as proteasome modulators and their role as anti‐cancer compounds

Accelerated formation of α-synuclein oligomers by concerted action of the 20S proteasome and familial Parkinson mutations

Contact Info

Product

Resources

About