title: Survivin modulates genes with divergent molecular functions and regulates proliferation of hematopoietic stem cells through Evi-1.
abstract: The inhibitor of apoptosis protein Survivin regulates hematopoiesis, although its mechanisms of regulation of hematopoietic stem cells (HSCs) remain largely unknown. While investigating conditional Survivin deletion in mice, we found that Survivin was highly expressed in phenotypically defined HSCs, and Survivin deletion in mice resulted in significantly reduced total marrow HSCs and hematopoietic progenitor cells. Transcriptional analysis of Survivin(-/-) HSCs revealed altered expression of multiple genes not previously linked to Survivin activity. In particular, Survivin deletion significantly reduced expression of the Evi-1 transcription factor indispensable for HSC function, and the downstream Evi-1 target genes Gata2, Pbx1 and Sall2. The loss of HSCs following Survivin deletion and impaired long-term HSC repopulating function could be partially rescued by ectopic Evi-1 expression in Survivin -/- HSCs. These data demonstrate that Survivin partially regulates HSC function by modulating the Evi-1 transcription factor and its downstream targets and identify new genetic pathways in HSCs regulated by Survivin.
authors.affiliation: Department of Pediatrics, Shimane University School of Medicine, Izumo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Fukuda
authors.affiliation: 1] Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hoggatt
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: P
authors.initials: P
authors.lastname: Singh
authors.affiliation: Department of Pediatrics, Shimane University School of Medicine, Izumo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Abe
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Speth
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: P
authors.initials: P
authors.lastname: Hu
authors.affiliation: Centre for Blood Research, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: E M
authors.initials: EM
authors.lastname: Conway
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL, USA.
authors.forename: G
authors.initials: G
authors.lastname: Nucifora
authors.affiliation: Department of Pediatrics, Shimane University School of Medicine, Izumo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Pelus
mesh_terms: D000483:Alleles; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002453:Cell Cycle; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D050989:GATA2 Transcription Factor / Q000378:metabolism; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011519:Proto-Oncogenes / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D000077022:Survivin; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C117749:Birc5 protein, mouse; D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D018398:Homeodomain Proteins; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; C499305:Mecom protein, mouse; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D012097:Repressor Proteins; C403266:Sall2 protein, mouse; D000077022:Survivin; D014157:Transcription Factors