DUB-2A, a new member of the DUB subfamily of hematopoietic deubiquitinating enzymes

Protein ubiquitination Is an important regulator of cytokine-activated sign al transduction pathways and hematopoietic cell growth. Protein ubiquitinat ion is controlled by the coordinate action of ubiquitin-conjugating enzymes and deubiquitinating enzymes. Recently a novel family of genes encoding gr owth-regulatory deubiquitinating enzymes (DUB-1 and DUB-2) has been identif ied. DUBs are immediate-early genes and are induced rapidly and transiently in response to cytokine stimuli. By means of polymerase chain reaction amp lification with degenerate primers for the DUB-2 complementary DNA, 3 murin e bacterial artificial chromosome (BAC) clones that contain DUB gene sequen ces were isolated. One BAC contained a novel DUB gene (DUB-2A) with extensi ve homology to DUB-2. Like DUB-1 and DUB-2, the DUB-2A gene consists of 2 e xons. The predicted DUB-2A protein is highly related to other DUBs througho ut the primary amino acid sequence, with a hypervariable region at its C-te rminus. In vitro, DUB-2A had functional deubiquitinating activity; mutation of its conserved amino acid residues abolished this activity. The 5 ' flan king sequence of the DUB-2A gene has a hematopoietic-specific functional en hancer sequence. It Is proposed that there are at least 3 members of the DU B subfamily (DUB-1, DUB-2, and DUB-2A) and that different hematopoietic cyt okines induce specific DUB genes, thereby initiating a cytokine-specific gr owth response.