Loss of the Amino-Terminal Helix-Loop-Helix Domain of the vav Proto-Oncogene Activates Its Transforming Potential

Abstract

vav, a novel human oncogene, was originally generated in vitro by replacement of its normal 5' coding sequences with sequences from pSV2neo DNA, cotransfected as a selectable marker (S. Katzav, D. Martin-Zanca, and M. Barbacid, EMBO J. 8:2283-2290, 1989). The vav proto-oncogene is normally expressed in cells of hematopoietic origin. To determine whether the 5' rearrangement of vav or its ectopic expression in NIH 3T3 cells contributes to its transforming potential, we isolated murine and human proto-vav cDNA clones as well as human genomic clones corresponding to the 5' end of the gene. Normal proto-vav was poorly transforming in NIH 3T3 cells, whereas truncation of its 5' end greatly enhanced its transforming activity. The relative failure of full-length proto-vav cDNA clones to transform NIH 3T3 cells indicates that the transforming activity of vav is not simply due to ectopic expression. Analysis of the predicted amino terminus of the vav proto-oncogene shows that it contains a helix-loop-helix domain and a leucine zipper motif similar to that of myc family proteins, though it lacks a basic region that is usually found adjacent to helix-loop-helix domains. Loss of the helix-loop-helix domain of proto-vav, either by truncation or by rearrangement with pSV2neo sequences, activates its oncogenic potential.

Single-cell transcriptional landscapes reveal HIV-1–driven aberrant host gene transcription as a potential therapeutic target

“…Therefore, there was no RAP1B truncation in the 1G2-RAP1B clone. Of note, an N-terminal truncation is known to increase the oncogenic potency of VAV1 (56). Overall, we showed that HIV-1-induced aberrant host gene transcription at the integration site leads to aberrant host protein expression.…”

Vav-2 controls NFAT-dependent transcription inB- but not T-lymphocytes

“…Oncogenic Vav‐1 contains a deletion of the CH domain and is mildly transforming towards 3T3 cells but unable to potentiate NFAT‐dependent transcription (Katzav et al ., 1991; Wu et al ., 1995). Deletion of the N‐terminal 187 amino acids of Vav‐1 substantially enhances transforming potential; however, this mutant is still unable to potentiate NFAT‐dependent transcription in Jurkat T cells (Lopez‐Lago et al ., 2000).…”

Signaling pathways activated by interferons

“…Another signaling molecule that is involved in Type I IFN signaling is the vav protoonco-gene (Vav). Vav is specifically expressed in cells of hematopoietic origin and contains src homology 2 (SH2) and src homology 3 (SH3) domains and guanine exchange factor motifs [99][100][101]. This protein undergoes tyrosine phosphorylation in response to a wide variety of stimuli in different cell types and participates in signaling induced by various cytokines (reviewed in [102][103][104]).…”