Degradation of Proto-oncoprotein c-Rel by the Ubiquitin-Proteasome Pathway

Chen, Eying; Hrdličková, Radmila; Nehyba, Jiřı́; Longo, Dan L.; Bose, Henry R.; Li, Chou-Chi H.

doi:10.1074/jbc.273.52.35201

Cited by 34 publications

(27 citation statements)

References 51 publications

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“…Ubiquitination of nNOS in Vivo-As expected from previous studies (12,18,19), lactacystin treatment of HEK 293 cells was found to cause a large increase in the level of immunodetectable Ub-protein conjugates (data not shown). Moreover, Ubprotein conjugates are known to be deubiquitinated by an NEM-sensitive pathway (20).…”

Section: Inhibition Of the Proteasome Leads To Accumulation Of Highersupporting

confidence: 58%

Ubiquitination of Neuronal Nitric-oxide Synthase in Vitro and in Vivo

Bender¹,

Demady

Osawa

2000

Journal of Biological Chemistry

109

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It is established that suicide inactivation of neuronal nitric-oxide synthase (nNOS) with guanidine compounds, or inhibition of the hsp90-based chaperone system with geldanamycin, leads to the enhanced proteolytic degradation of nNOS. This regulated proteolysis is mediated, in part, by the proteasome. We show here with the use of human embryonic kidney 293 cells transfected with nNOS that inhibition of the proteasome with lactacystin leads to the accumulation of immunodetectable higher molecular mass forms of nNOS. Some of these higher molecular mass forms were immunoprecipitated by an anti-ubiquitin antibody, indicating that they are nNOS-polyubiquitin conjugates. Moreover, the predominant nNOS-ubiquitin conjugate detected in human embryonic kidney 293 cells, as well as in rat brain cytosol, migrates on SDS-polyacrylamide gels with a mobility near that for the native monomer of nNOS and likely represents a conjugate containing a few or perhaps one ubiquitin. Studies in vitro with the use of 125 I-ubiquitin and reticulocyte extracts could mimic this ubiquitination reaction, which was dependent on ATP. The hemedeficient monomeric form of nNOS is preferentially ubiquitinated over that of the heme-sufficient functionally active homodimer. Thus, we have shown for the first time that ubiquitination of nNOS occurs and is likely involved in the regulated proteolytic removal of nonfunctional enzyme.

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Section: Inhibition Of the Proteasome Leads To Accumulation Of Highersupporting

confidence: 58%

Ubiquitination of Neuronal Nitric-oxide Synthase in Vitro and in Vivo

Bender¹,

Demady

Osawa

2000

Journal of Biological Chemistry

109

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“…Similarly, although a conserved Cys residue (Cys-35) within a sequence critical for DNA binding has been shown to undergo redox regulation in vitro , there is no substantial evidence that v-Rel (or other Rel proteins) undergo such regulation in vivo. Finally, Chen et al (1998) have recently suggested that v-Rel undergoes reduced ubiquitin-proteasomemediated degradation as compared to c-Rel.…”

Section: Post-translational Modi®cations Of V-relmentioning

confidence: 99%

Multiple mutations contribute to the oncogenicity of the retroviral oncoprotein v-Rel

1999

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The avian Rev-T retrovirus encodes the v-Rel oncoprotein, which is a member of the Rel/NF-kB transcription factor family. v-Rel induces a rapidly fatal lymphoma/ leukemia in young birds, and v-Rel can transform and immortalize a variety of avian cell types in vitro. Although Rel/NF-kB transcription factors have been associated with oncogenesis in mammals, v-Rel is the only member of this family that is frankly oncogenic in animal model systems. The potent oncogenicity of v-Rel is the consequence of a number of mutations that have altered its activity and regulation: for example, certain mutations decrease its ability to be regulated by IkBa, change its DNA-binding site speci®city, and endow it with new transactivation properties. The study of v-Rel will continue to increase our knowledge of how cellular Rel proteins contribute to oncogenesis by a ecting cell growth, altering cell-cycle regulation, and blocking apoptosis. This review will discuss biological and molecular activities of v-Rel, with particular attention to how these activities relate to structure ± function aspects of the Rel/NF-kB transcription factors.

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“…It is possible that inhibitory phosphorylations within the RelA transactivation domain, such as at Thr-505, also have a role in shutting down the NF-kB response. IKKa also regulates c-Rel turnover (Lawrence et al, 2005), and c-Rel is also subject to ubiquitination between residues 427 and 480 that promotes c-Rel proteolysis (Chen et al, 1998). The sites of any modifications of c-Rel that mediate these events and whether they are linked, are not known.…”

Section: Termination Of the Nf-jb Responsementioning

confidence: 99%