The deubiquitinating enzyme DUB-2 prolongs cytokine-induced signal transducers and activators of transcription activation and suppresses apoptosis following cytokine withdrawal

Cytokines, such as interleukin-2 (IL-2), activate intracellular signaling p athways via rapid tyrosine phosphorylation of their receptors, resulting in the activation of many genes involved in cell growth and survival. The deu biquitinating enzyme DUB-2 is induced in response to IL-2 but as yet its fu nction has not been determined. The results of this study show that DUB-2 i s expressed in human T-cell lymphotropic virus-I(HTLV-1)-transformed T cell s that exhibit constitutive activation of the IL-2 JAK/STAT (signal transdu cers and activators of transcription) pathway, and when expressed in Ba/F3 cells DUB-2 markedly prolonged IL-2-induced STAT5 phosphorylation. Although DUB-2 did not enhance IL-2-mediated proliferation, when withdrawn from gro wth factor, cells expressing DUB-2 had sustained STAT5 phosphorylation and enhanced expression of IL-2-induced genes cis and c-myc. Moreover, DUB-2 ex pression markedly inhibited apoptosis induced by cytokine withdrawal allowi ng cells to survive. Taken together these data suggest that DUB-2 can enhan ce signaling through the JAK/STAT pathway, prolong lymphocyte survival, and , when constitutively expressed, may contribute to the activation of the JA K/STAT pathway observed in some transformed cells.