Modes of regulation of ubiquitin-mediated protein degradation

Kornitzer, Daniel; Ciechanover, Aaron

doi:10.1002/(sici)1097-4652(200001)182:1<1::aid-jcp1>3.0.co;2-v

Cited by 237 publications

(166 citation statements)

References 133 publications

(105 reference statements)

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“…The anti-Rac antibody used detected mutant and wild-type Rac with the same sensitivity (data not shown). Moreover, we determined the amount of Rho proteins by 14 C glucosylation with Clostridium difficile toxin B, which modifies Rho, Rac, and Cdc42 by monoglucosylation at threonine-37 and threonine-35 (13) (Fig. 1C and D).…”

Section: Resultsmentioning

confidence: 99%

“…Virtually all proteins degraded by the 26S proteasome are labeled with ubiquitin (14). Ubiquitin is a small protein (about 8 kDa) which is transferred onto lysine residues of the target protein by specific ubiquitin ligases (14).…”

Section: Discussionmentioning

confidence: 99%

“…Ubiquitin is a small protein (about 8 kDa) which is transferred onto lysine residues of the target protein by specific ubiquitin ligases (14). Subsequently, another ubiquitin molecule is linked to the first and so on.…”

Section: Discussionmentioning

confidence: 99%

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Proteasomal Degradation of Cytotoxic Necrotizing Factor 1-Activated Rac

Lerm

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Fritz³

et al. 2002

Infect Immun

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Proteasomal Degradation of Cytotoxic Necrotizing Factor 1-Activated Rac

Lerm

Pop

Fritz³

et al. 2002

Infect Immun

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“…Subsequent processive transfer of additional activated ubiquitin molecules and their conjugation to previously attached moieties, generates a polyubiquitin chain that serves as a degradation signal for the proteasome. Binding of the substrate to E3 plays an essential role in speci®c substrate recognition (for recent reviews on the ubiquitinproteasome pathway, see, for example, Kornitzer and Ciechanover, 2000;Voges et al, 1999). In most cases, the ®rst ubiquitin molecule is transferred to an e-NH 2 group of an internal Lysine residue of the target protein.…”

Section: Introductionmentioning

confidence: 99%

Degradation of the E7 human papillomavirus oncoprotein by the ubiquitin-proteasome system: targeting via ubiquitination of the N-terminal residue

et al. 2000

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The E7 oncoprotein of the high risk human papillomavirus type 16 (HPV-16), which is etiologically associated with uterine cervical cancer, is a potent immortalizing and transforming agent. It probably exerts its oncogenic functions by interacting and altering the normal activity of cell cycle control proteins such as p21 WAF1 , p27 KIP1 and pRb, transcriptional activators such as TBP and AP-1, and metabolic regulators such as M2-pyruvate kinase (M2-PK). Here we show that E7 is a short-lived protein and its degradation both in vitro and in vivo is mediated by the ubiquitin-proteasome pathway. Interestingly, ubiquitin does not attach to any of the two internal Lysine residues of E7. Substitution of these residues with Arg does not a ect the ability of the protein to be conjugated and degraded; in contrast, addition of a Myc tag to the N-terminal but not to the C-terminal residue, stabilizes the protein. Also, deletion of the ®rst 11 amino acid residues stabilizes the protein in cells. Taken together, these ®ndings strongly suggest that, like MyoD and the Epstein Barr Virus (EBV) transforming Latent Membrane Protein 1 (LMP1), the ®rst ubiquitin moiety is attached linearly to the free N-terminal residue of E7. Additional ubiquitin moieties are then attached to an internal Lys residue of the previously conjugated molecule. The involvement of E7 in many diverse and apparently unrelated processes requires tight regulation of its function and cellular level, which is controlled in this case by ubiquitin-mediated proteolysis. Oncogene (2000) 19, 5944 ± 5950.

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“…Experiments have implicated ubiquitination or ubiquitin dependent protein degradation in virtually every facet of cellular regulation, including: cell cycle progression, di erentiation, stress responses, DNA repair, signal transduction, gene regulation, control of proto-oncogenes, antigen presentation, and removal of damaged proteins (Haas and Siepmann, 1997a,b;Jahngen-Hodge et al, 1997;Johnston et al, 1998;Kornitzer and Ciechanover, 2000;Obin et al, 1999;Shang et al, 1997a; for reviews see Ciechanover, 1994;Ciechanover et al, 1985;Hochstrasser, 1996;Huang et al, 1995;Jentsch and Schlenker, 1995;Shang et al, 1997b;Shang and Taylor, 1995;Varshavsky, 1997). Most, but not all, of these functions are accomplished by degrading or preventing the degradation of relevant regulatory proteins.…”

Section: Introductionmentioning

confidence: 99%

Ubiquitination capabilities in response to neocarzinostatin and H2O2 stress in cell lines from patients with ataxia-telangiectasia

et al. 2002

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The human genetic disorder ataxia-telangiectasia (A-T) is due to lack of functional ATM, a protein kinase which is involved in cellular responses to DNA double strand breaks (DSBs) and possibly other oxidative stresses, as well as in regulation of several fundamental cellular functions. Studies regarding responses in A-T cells to the induction of DSBs utilize ionizing radiation or radiomimetic chemicals, such as neocarzinostatin (NCS), which induce DNA DSBs. This critical DNA lesion activates many defense systems, such as the cell cycle checkpoints. The cell cycle is also regulated through a timed and coordinated degradation of regulatory proteins via the ubiquitin pathway. Our recent studies indicate that the ubiquitin pathway is in¯uenced by the cellular redox status and that it is the major cellular pathway for removal of oxidized proteins. Accordingly, we hypothesized that the absence of a functional ATM protein might involve perturbations to the ubiquitin pathway as well. We show here that upon treatment with NCS, there was a transient 50 ± 70% increase in endogenous ubiquitin conjugates in A-T and wt lymphoblastoid cells. Ubiquitin conjugation capabilities per se and levels of substrates for conjugation were also similarly enhanced in wt and A-T cells upon NCS treatment. We also compared the ubiquitination response in A-T and wt cells using H 2 O 2 as the stress, in view of preexisting evidence of the e ects of H 2 O 2 on ubiquitination capabilities in other types of cells. As with NCS treatment, there was an &45% increase in endogenous ubiquitin conjugates by 2 ± 4 h after exposure to H 2 O 2 . Both cell types showed a rapid 50 ± 150% increase in de novo formed 125 I-ubiquitin conjugates. As compared with wt cells, unexposed A-T cells had higher endogenous levels of conjugates and enhanced conjugation capability. However, A-T cells mounted a more muted ubiquitination response to the stress. The enhanced ubiquitin conjugation in unstressed A-T cells and attenuated ability of these cells to respond to stress are consistent with the A-T cells being under oxidative stress and with their having aǹ aged' phenotype. The indication that ubiquitin conjugate levels and ubiquitin conjugation capabilities are enhanced upon oxidative stress without signi®cant changes in GSSG/GSH ratios indicates that assays of ubiquitination provide a sensitive measure of cellular stress. The data also add support to the impression that potentiated ubiquitination response to mild oxidative stress is a generalizable phenomenon.

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Modes of regulation of ubiquitin-mediated protein degradation

Cited by 237 publications

References 133 publications

Proteasomal Degradation of Cytotoxic Necrotizing Factor 1-Activated Rac

Proteasomal Degradation of Cytotoxic Necrotizing Factor 1-Activated Rac

Degradation of the E7 human papillomavirus oncoprotein by the ubiquitin-proteasome system: targeting via ubiquitination of the N-terminal residue

Ubiquitination capabilities in response to neocarzinostatin and H2O2 stress in cell lines from patients with ataxia-telangiectasia

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