DUB-1, a deubiquitinating enzyme with growth-suppressing activity

Cytokines regulate cell growth by inducing the expression of specific target genes. Using the differential display method, we have cloned a cytokine-inducible immediate early gene, DUE-I (for deubiquitinating enzyme), DUE-I is related to members of the UBP superfamily of deubiquitinating enzymes, which includes the oncoprotein Tre-2. A glutathione S-transferase-DUB-1 fusion protein cleaved ubiquitin from a ubiquitin-beta-galactosidase protein. When a conserved cysteine residue of DUE-I, required for ubiquitin specific thiol protease activity, was mutated to serine (C60S), deubiquitinating activity was abolished, Continuous expression of DUE-I from a steroid-inducible promoter induced growth arrest in the G(1) phase of the cell cycle, Cells arrested by DUE-I expression remained viable and resumed proliferation upon steroid withdrawal, Our results suggest that DUE-I regulates cellular growth by modulating either the ubiquitin-dependent proteolysis or the ubiquitination state of an unknown growth regulatory factor(s).