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Vav1 is a signal transducer protein that functions as a guanine nucleotide exchange factor for the Rho/Rac GTPases in the hematopoietic system where it is exclusively expressed. Recently, Vav1 was shown to be involved in several human malignancies including neuroblastoma, lung cancer, and pancreatic ductal adenocarcinoma (PDA). Although some factors that affect  vav1  expression are known, neither the physiological nor pathological regulation of  vav 1 expression is completely understood. We demonstrate herein that mutations in putative transcription factor binding sites at the  vav 1 promoter affect its transcription in cells of different histological origin. Among these sites is a consensus site for c-Myb, a hematopoietic-specific transcription factor that is also found in Vav1-expressing lung cancer cell lines. Depletion of c-Myb using siRNA led to a dramatic reduction in  vav 1 expression in these cells. Consistent with this, co-transfection of c-Myb activated transcription of a  vav1  promoter-luciferase reporter gene construct in lung cancer cells devoid of Vav1 expression. Together, these results indicate that c-Myb is involved in  vav 1 expression in lung cancer cells. We also explored the methylation status of the  vav 1 promoter. Bisulfite sequencing revealed that the  vav 1 promoter was completely unmethylated in human lymphocytes, but methylated to various degrees in tissues that do not normally express  vav 1. The  vav 1 promoter does not contain CpG islands in proximity to the transcription start site; however, we demonstrated that methylation of a CpG dinucleotide at a consensus Sp1 binding site in the  vav 1 promoter interferes with protein binding  in vitro . Our data identify two regulatory mechanisms for  vav 1 expression: binding of c-Myb and CpG methylation of 5′ regulatory sequences. Mutation of other putative transcription factor binding sites suggests that additional factors regulate  vav1  expression as well.

Human Vav1 Expression in Hematopoietic and Cancer Cell Lines Is Regulated by c-Myb and by CpG Methylation