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, DUB-1 (for deubiquitinating enzyme). DUB-1 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 DUB-1, required for ubiquitin-specific thiol protease activity, was mutated to serine (C60S), deubiquitinating activity was abolished. Continuous expression of DUB-1 from a steroid-inducible promoter induced growth arrest in the G1 phase of the cell cycle. Cells arrested by DUB-1 expression remained viable and resumed proliferation upon steroid withdrawal. Our results suggest that DUB-1 regulates cellular growth by modulating either the ubiquitin-dependent proteolysis or the ubiquitination state of an unknown growth regulatory factor(s).
Zhu
Y
Y
Division of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Carroll
M
M
Papa
F R
FR
Hochstrasser
M
M
D'Andrea
A D
AD
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D010450:Endopeptidases; D017781:Genes, Immediate-Early; D006131:Growth Inhibitors / Q000235:genetics* / Q000502:physiology*; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000502:physiology*; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014452:Ubiquitins / Q000378:metabolism*
D017931:DNA Primers; D018076:DNA, Complementary; D006131:Growth Inhibitors; D017874:Immediate-Early Proteins; D007377:Interleukin-3; D012333:RNA, Messenger; D014452:Ubiquitins; C099271:Dub1 protein, mouse; D010450:Endopeptidases