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J Biol Chem, Vol. 273, Issue 52, 35201-35207, December 25, 1998

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

Eying Chen, Radmila Hrdlickova^§, Jiri Nehyba^§, Dan L. Longo, Henry R. Bose Jr.^§, and Chou-Chi H. Li

From the  Intramural Research Support Program, SAIC Frederick, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, the ^§ Department of Microbiology and Institute for Cellular and Molecular Biology, University of Texas, Austin, Texas 78712, and the  NIA, National Institutes of Health, Gerontology Research Center, Baltimore, Maryland 21224

The c-rel proto-oncogene product, c-Rel, belongs to the Rel/NF-B transcription factor family, which regulates a large variety of cellular functions. The activation of NF-B involves the degradation of the inhibitor, IB, 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-B. 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.

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