RESUMO
The mouse zinc-finger gene Zfp521 (also known as ecotropic viral insertion site 3; Evi3; and ZNF521 in humans) has been identified as a B-cell proto-oncogene, causing leukemia in mice following retroviral insertions in its promoter region that drive Zfp521 over-expression. Furthermore, ZNF521 is expressed in human hematopoietic cells, and translocations between ZNF521 and PAX5 are associated with pediatric acute lymphoblastic leukemia. However, the regulatory factors that control Zfp521 expression directly have not been characterized. Here we demonstrate that the transcription factors SPI1 (PU.1) and HOXC13 synergistically regulate Zfp521 expression, and identify the regions of the Zfp521 promoter required for this transcriptional activity. We also show that SPI1 and HOXC13 activate Zfp521 in a dose-dependent manner. Our data support a role for this regulatory mechanism in vivo, as transgenic mice over-expressing Hoxc13 in the fetal liver show a strong correlation between Hoxc13 expression levels and Zfp521 expression. Overall these experiments provide insights into the regulation of Zfp521 expression in a nononcogenic context. The identification of transcription factors capable of activating Zfp521 provides a foundation for further investigation of the regulatory mechanisms involved in ZFP521-driven cell differentiation processes and diseases linked to Zfp521 mis-expression.
Assuntos
Proteínas de Homeodomínio/genética , Leucemia/genética , Proteínas Proto-Oncogênicas/genética , Transativadores/genética , Fatores de Transcrição/genética , Ativação Transcricional/genética , Animais , Linfócitos B/metabolismo , Diferenciação Celular/genética , Regulação Leucêmica da Expressão Gênica , Proteínas de Homeodomínio/biossíntese , Humanos , Leucemia/patologia , Camundongos , Camundongos Transgênicos , Fator de Transcrição PAX5/biossíntese , Fator de Transcrição PAX5/genética , Regiões Promotoras Genéticas , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/biossíntese , Retroviridae/genética , Transativadores/biossíntese , Fatores de Transcrição/biossínteseRESUMO
Leukemia arises due to the dysregulated proliferation of hematopoietic progenitor cells. Errors in the multi-step commitment process result in excessive numbers of immature lymphocytes, causing malignant disease. Genes involved in the differentiation of lymphocytes are often associated with leukemia. One such gene, Zfp521, has been found to cause B-cell leukemia in mice when over-expressed. The role of Zfp521 in B-cell differentiation, and the mechanisms by which it leads to leukemic transformation, are unclear. In this study we report that Zfp521 knockdown causes apoptosis in a B-cell culture system and promotes down-regulation of genes acting at late stages of B-cell differentiation. We identify Pax5 and cyclin D1 as Zfp521 target genes, and suggest that excessive B-cell proliferation observed in mice with retroviral insertions near the Zfp521 gene is due to an up-regulation of cyclin D1 in B-cells. Overall, these results suggest links between dysregulated Zfp521 and B-cell survival.