DUB-3, a Cytokine-inducible Deubiquitinating Enzyme That Blocks Proliferation

Abstract

Previous studies have identified the DUB family of cytokine-regulated murine deubiquitinating enzymes, which play a role in the control of cell proliferation and survival. Through data base analyses and cloning, we have identified a human cDNA (DUB-3) that shows significant homology to the known murine DUB family members. Northern blotting has shown expression of this gene in a number of tissues including brain, liver, and muscle, with two transcripts being apparent (1.6 and 1.7 kb). In addition, expression was observed in cell lines including those derived from a number of hematopoietic tumors such as the Burkitt's lymphoma cell line RAJI. We have also demonstrated that DUB-3, which was shown to be an active deubiquitinating enzyme, is induced in response to interleukin-4 and interleukin-6 stimulation. Finally, we have demonstrated that constitutive expression of DUB-3 blocks proliferation and can initiate apoptosis in both IL-3-dependent Ba/F3 cells and NIH3T3 fibroblasts. These findings suggest that human DUB-3, like the murine DUB family members, is transiently induced in response to cytokines and can, when constitutively expressed, block growth factor-dependent proliferation.

The Deubiquitinating Enzyme USP17 Is Highly Expressed in Tumor Biopsies, Is Cell Cycle Regulated, and Is Required for G1-S Progression

“…Several lines of evidence have implicated these enzymes in the regulation of cell growth and survival. Constitutive expression of murine DUB-1 has been shown to induce G 1 cell cycle arrest, whereas DUB-2 expression can markedly inhibit apoptosis following cytokine withdrawal (15,17,19,20). In addition, we have confirmed that constitutive overexpression of human USP17 blocks growth factor-dependent cell proliferation (20).…”

Deubiquitinases in cancer: new functions and therapeutic options

“…Examples of transcriptional regulation are those affecting mouse DUB-1, DUB-2 and DUB-3, which are induced by inflammatory cytokines (Jaster et al, 1999;Burrows et al, 2004;Baek, 2006), and CYLD that is induced by the activation of the nuclear factor-kB (NF-kB) and MAPK Kinase 3/6 (MKK3/6)-p38 pathways (Yoshida et al, 2005). In addition, many DUB functions are tightly controlled by post-translational modifications .…”

The regulation of snail: on the ubiquitin edge

“…Dub3 belongs to the USP group. Whereas Dub1 and Dub2 were identified in mice, Dub3 is their human counterpart [31] . This family of growth-regulatory deubiquitinating enzymes are immediate-early genes and are induced rapidly and transiently in response to cytokine stimuli [32] .…”

“…IL-6 is also identified as a major cytokine secreted by BLBC cells and is essential for the CSC-like characteristic of BLBC [41] . Interestingly, Dub3 activity and expression, at both the mRNA and protein levels, can be induced by IL-6 through the JAK/STAT3 signaling pathway [31,38,39] . Consistent with this, we also found that IL-6 rapidly induces Dub3 expression, exerting a maximum effect at 2hr [38] .…”