Evi3, a zinc-finger protein related to EBFAZ, regulates EBF activity in B-cell leukemia.
Retroviral insertions that activate proto-oncogenes are a primary cause of tumors in certain strains of mice. The AKXD recombinant inbred mice are predisposed to a variety of leukemias and lymphomas as a result of viral integration. One common insertion site, the ecotropic viral insertion site 3 (Evi3), has been implicated in most B-cell tumors in the AKXD-27 strain. The Evi3 gene encodes a zinc-finger protein with sequence similarity to the Early B-cell Factor-Associated Zinc-finger gene (EBFAZ). We show that the Evi3 gene is overexpressed in several tumors with viral insertions at Evi3, which results in the upregulation of Early B-cell Factor (EBF)-target gene expression, suggesting that Evi3 modulates EBF activity. Reconstitution of primary leukemia cells showed that these tumors express high densities of the B-cell surface proteins CD19 and CD38, which are EBF targets. Using a transactivation assay, we show that the terminal six zinc-fingers of Evi3 are required for modification of EBF activity. This is the first evidence that Evi3 expression in tumors alters the level of EBF target genes, and the first characterization of the Evi3 protein domains required for modulation of EBF activity. Further, these data imply that Evi3 misexpression initiates tumorigenesis by perturbing B-cell development via an interaction with EBF.
Hentges
Kathryn E
KE
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Weiser
Keith C
KC
Schountz
Tony
T
Woodward
Lanette S
LS
Morse
Herbert C
HC
Justice
Monica J
MJ
D036541:ADP-ribosyl Cyclase / Q000032:analysis / Q000096:biosynthesis; D051997:ADP-ribosyl Cyclase 1; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D018941:Antigens, CD19 / Q000032:analysis / Q000096:biosynthesis; D051925:CD79 Antigens; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D015448:Leukemia, B-Cell / Q000235:genetics* / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D051757:PAX5 Transcription Factor; D011947:Receptors, Antigen, B-Cell / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D016335:Zinc Fingers / Q000235:genetics / Q000502:physiology
D015703:Antigens, CD; D018941:Antigens, CD19; D051925:CD79 Antigens; D002352:Carrier Proteins; C497882:Cd79a protein, mouse; C497884:Cd79b protein, mouse; D004268:DNA-Binding Proteins; C489921:Ebf1 protein, mouse; C484557:Ebfaz protein, mouse; C472572:Evi3 protein, mouse; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D011947:Receptors, Antigen, B-Cell; D015534:Trans-Activators; D014157:Transcription Factors; D036541:ADP-ribosyl Cyclase; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1