vav, a novel human oncogene derived from a locus ubiquitously expressed in hematopoietic cells.

Abstract

A novel human oncogene, designated vav, was generated by a genetic rearrangement during gene transfer assays. The vav oncogene directs the synthesis of a 3.0 kb mRNA from which we isolated a 2.8 kb‐long complementary DNA copy. Nucleotide sequence analysis of this vav oncogene cDNA clone revealed that its 5′ 167 bp were derived from pSV2neo DNA cotransfected as a selectable marker during gene transfer. The remaining 2597 bp were unrelated to genes included in current data banks, indicating that the vav oncogene is likely to be derived from a novel human locus. The vav oncogene cDNA clone encompasses a 2391 bp long open reading frame (ORF) capable of directing the synthesis of a 797 amino acid long polypeptide. The predicted vav oncogene protein sequence exhibits several motifs reminiscent of transcriptional factors. They include a highly acidic amino‐terminal region separated from two putative nuclear localization signals by a proline‐rich sequence, presumably a hinge region. In addition, we identified two zinc‐finger‐like domains, one of which conforms to the canonical pattern Cys‐X2‐Cys‐X13‐Cys‐X2‐Cys previously found to confer trans‐activating activity to the adenovirus E1A protein. Transcription of its normal allele, the vav proto‐oncogene, has been exclusively observed in cells of hematopoietic origin, including those of erythroid, lymphoid and myeloid lineages. These findings raise the possibility that this novel locus might play an important role in hematopoiesis.

Caspase-dependent cleavage and inactivation of the Vav1 proto-oncogene product during apoptosis prevents IL-2 transcription

“…Both cleavage sites are located within the acidic domain and chop o the N-terminal part containing a CH domain (Katzav, 1995). In this context it is noteworthy that the oncogenic form of Vav1 arises from the deletion of 67 N-terminal amino acids from Vav1 and induces tumors in nude mice (Katzav et al, 1989;Coppola et al, 1991). Although this N-terminal truncation of Vav1 induces its oncogenic activity, the ability to induce NF-AT-dependent transcription is reduced (Wu et al, 1995).…”

“…This 95 kDa protein displays a wide variety of structural motifs including a N-terminal calponin homology (CH) domain, an acidic domain (AD), a Dbl-homology (DH) domain, a putative bipartite nuclear localization signal (NLS), a pleckstrin homology (PH) domain, a cysteine-rich domain (CR) and one SH2-domain anked by two SH3 domains (Romero and Fischer, 1996). Its expression is restricted to cells of haematopoietic origin (Katzav et al, 1989). Targeted gene disruption revealed the importance of Vav1 for receptor-mediated proliferation and TCR-mediated positive selection (Fischer et al, 1995;Tarakhovsky et al, 1995;Zhang et al, 1995;Turner et al, 1997).…”

Cbl-b, a member of the Sli-1/c-Cbl protein family, inhibits Vav-mediated c-Jun N-terminal kinase activation

“…The vav gene was ®rst identi®ed by virtue of its oncogenic activation during the course of gene transfer assays (Katzav et al, 1989). Its normal allele, the vav proto-oncogene, encodes a 95 kDa polypeptide that harbors a complex array of structural domains, including leucine-rich, acidic, Dbl-homology (DH), pleckstrin-homology (PH), cysteine-rich, SH3 and SH2 domains (for a review, see Bustelo 1996).…”

“…The important role of this gene during mitogenic and ontogenic processes was demonstrated by both cell biology and genetic experiments. Thus, it has been shown that Vav can induce high levels of morphological transformation in rodent ®broblasts after deletion of N-terminal sequences (Katzav et al, 1989;Coppola et al, 1991). Moreover, disruption of the vav locus by homologous recombination techniques results in severe signaling defects of primary antigen receptors, leading to abnormal lymphocyte proliferation and lymphocytopenia (Fisher et al, 1995;Tarakhovski et al, 1995;Zhang et al, 1995).…”

Characterization, expression and chromosomal localization of a human gene homologous to the mouse Lsc oncogene, with strongest expression in hematopoetic tissues

“…It was shown that both the GEF activity and the transforming activity of the Dbl protein was localized to a 240 amino acid motif between residues 498 and 738 in the protein (Hart et al, 1994). An emerging group of proteins conferring homology to this 240 amino acid motif in the Dbl oncogene has been identi®ed including Vav (Katzav et al, 1989), Ect-2 (Miki et al, 1993), Lbc (Toksoz and Williams, 1994), Lfc (Whitehead et al, 1995), Tim (Chan et al, 1994), Tiam (Habets et al, 1994), Cdc24 (from Saccharomysis cerevisia; Drubin, 1991), the breakpoint cluster region protein (Bcr; Hariharan and Adams, 1987), and the mammalian ras guanidine releasing factor (Shou et al, 1992).…”