title: Transcriptional regulation of the proto-oncogene Zfp521 by SPI1 (PU.1) and HOXC13.
abstract: 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.
authors: Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.|The Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Molecular and Clinical Medicine, Kunming Medical University, Kunming, Yunnan Province, 650500, People's Republic of China.
authors: Ming
authors: M
authors: Yu
authors: Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors: Salma
authors: S
authors: Al-Dallal
authors: Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.|Molecular Biomedicine Program, Program in Biomolecular Research, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, Saudi Arabia.
authors: Latifa
authors: L
authors: Al-Haj
authors: Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors: Shiraj
authors: S
authors: Panjwani
authors: Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors: Akina S
authors: AS
authors: McCartney
authors: Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors: Sarah M
authors: SM
authors: Edwards
authors: Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors: Pooja
authors: P
authors: Manjunath
authors: Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK.
authors: Catherine
authors: C
authors: Walker
authors: Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425.
authors: Alexander
authors: A
authors: Awgulewitsch
authors: Faculty of Life Sciences, University of Manchester, Manchester, M13 9PT, UK. kathryn.hentges@manchester.ac.uk.
authors: Kathryn E
authors: KE
authors: Hentges
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D051757:PAX5 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D018398:Homeodomain Proteins; D051757:PAX5 Transcription Factor; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099232:Proto-Oncogene Protein Spi-1; C472572:Evi3 protein, mouse; C410305:HOXC13 protein, human; C000715470:MAS1 protein, human; C497281:PAX5 protein, human
keywords: AKXD mice; B-cell differentiation; B-cell leukemia; Evi3; ZNF521