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 pathways via rapid tyrosine phosphorylation of their receptors, resulting in the activation of many genes involved in cell growth and survival. The deubiquitinating enzyme DUB-2 is induced in response to IL-2 but as yet its function has not been determined. The results of this study show that DUB-2 is expressed in human T-cell lymphotropic virus-I (HTLV-1)-transformed T cells that exhibit constitutive activation of the IL-2 JAK/STAT (signal transducers 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 Although DUB-2 did not enhance IL-2-mediated proliferation, when withdrawn from growth factor, cells expressing DUB-2 had sustained STAT5 phosphorylation and enhanced expression of IL-2-induced genes cis and c-myc. Moreover, DUB-2 expression markedly inhibited apoptosis induced by cytokine withdrawal allowing cells to survive. Taken together these data suggest that DUB-2 can enhance signaling through the JAK/STAT pathway, prolong lymphocyte survival, and, when constitutively expressed, may contribute to the activation of the JAK/STAT pathway observed in some transformed cells.
Migone
T S
TS
DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, CA, USA.
Humbert
M
M
Rascle
A
A
Sanden
D
D
D'Andrea
A
A
Johnston
J A
JA
D017209:Apoptosis; D002460:Cell Line; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D010450:Endopeptidases; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology*; D007376:Interleukin-2 / Q000494:pharmacology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism* / Q000473:pathology; D007976:Leupeptins / Q000494:pharmacology; D008894:Milk Proteins; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology; D015533:Transcriptional Activation; D014162:Transfection; D014452:Ubiquitins / Q000378:metabolism
D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D007376:Interleukin-2; D007976:Leupeptins; D008894:Milk Proteins; D009097:Multienzyme Complexes; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014452:Ubiquitins; C103857:Dub2 protein, mouse; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde