UBPY - A GROWTH-REGULATED HUMAN UBIQUITIN ISOPEPTIDASE

The ubiquitin pathway has been implicated in the regulation of the abu ndance of proteins that control cell growth and proliferation. We have identified and characterized a novel human ubiquitin isopeptidase, UB PY, which both as a recombinant protein and upon immunoprecipitation f rom cell extracts is able to cleave linear or isopeptide-linked ubiqui tin chains. UBPY accumulates upon growth stimulation of starved human fibroblasts, and its levels decrease in response to growth arrest indu ced by cell-cell contact. Inhibition of UBPY accumulation by antisense plasmid microinjection prevents fibroblasts from entering S-phase in response to serum stimulation. By increasing or decreasing the cellula r abundance of UBPY or by overexpressing a catalytic site mutant, we d etect substantial changes in the total pattern of protein ubiquitinati on, which correlate stringently with cell proliferation. Our results s uggest that UBPY plays a role in regulating the overall function of th e ubiquitin-proteasome pathway. Affecting the function of a specific U BP lit vivo could provide novel tools for controlling mammalian cell p roliferation.