Degradation of proto-oncoprotein c-Rel by the ubiquitin-proteasome pathway.
The c-rel proto-oncogene product, c-Rel, belongs to the Rel/NF-kappaB transcription factor family, which regulates a large variety of cellular functions. The activation of NF-kappaB involves the degradation of the inhibitor, IkappaB, through the ubiquitin-proteasome (Ub-Pr)-mediated pathway. Here we report that the turnover of c-Rel is also regulated by the Ub-Pr pathway, thus adding another level of complexity to the regulation of NF-kappaB. High molecular weight ubiquitinated c-Rel conjugates are detected in cells and accumulate in cells treated with proteasome inhibitors. In a cell-free in vitro degradation assay, c-Rel is degraded specifically through the Ub-Pr pathway. N-terminally truncated c-Rel is readily degraded, implying the dispensability of N-terminal sequence; in contrast, a series of deletion mutants missing C-terminal sequences display a reduced susceptibility to the degradation. Interestingly, the sequence between residues 118 and 171 of c-Rel, i.e. the region immediately following the c-Rel/v-Rel homology domain, appears to play an important role in mediating ubiquitin conjugation and the subsequent degradation. Together with our previous study showing an elevated tumorigenic potential for C-terminally truncated mutants, our data suggest that the C-terminal domain of c-Rel plays an important role in mediating c-Rel degradation and growth control.
Chen
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Intramural Research Support Program, SAIC Frederick, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA.
Hrdlickova
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Nehyba
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Longo
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Bose
H R
HR
Li
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D016475:3T3 Cells; D000818:Animals; D001717:Birds; D019556:COS Cells; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015368:Human T-lymphotropic virus 1 / Q000254:growth & development; D016393:Lymphoma, B-Cell / Q000378:metabolism; D051379:Mice; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D014452:Ubiquitins / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; C000715470:MAS1 protein, human; D009097:Multienzyme Complexes; D016328:NF-kappa B; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D011994:Recombinant Proteins; D014452:Ubiquitins; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex