title: A network including TGFβ/Smad4, Gata2, and p57 regulates proliferation of mouse hematopoietic progenitor cells.
abstract: Transforming growth factor β (TGFβ) is a potent inhibitor of hematopoietic stem and progenitor cell proliferation. However, the precise mechanism for this effect is unknown. Here, we have identified the transcription factor Gata2, previously described as an important regulator of hematopoietic stem cell function, as an early and direct target gene for TGFβ-induced Smad signaling in hematopoietic progenitor cells. We also report that Gata2 is involved in mediating a significant part of the TGFβ response in primitive hematopoietic cells. Interestingly, the cell cycle regulator and TGFβ signaling effector molecule p57 was found to be upregulated as a secondary response to TGFβ. We observed Gata2 binding upstream of the p57 genomic locus, and importantly, loss of Gata2 abolished TGFβ-stimulated induction of p57 as well as the resulting growth arrest of hematopoietic progenitors. Our results connect key molecules involved in hematopoietic stem cell self-renewal and reveal a functionally relevant network, regulating proliferation of primitive hematopoietic cells.
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: Matilda
authors.initials: M
authors.lastname: Billing
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Rörby
authors.affiliation: Stem Cell Group, University College London Cancer Institute, London, United Kingdom.
authors.forename: Gillian
authors.initials: G
authors.lastname: May
authors.affiliation: Stem Cell Group, University College London Cancer Institute, London, United Kingdom.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Tipping
authors.affiliation: Division of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: Shamit
authors.initials: S
authors.lastname: Soneji
authors.affiliation: Stem Cell Group, University College London Cancer Institute, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Brown
authors.affiliation: Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland.
authors.forename: Marjo
authors.initials: M
authors.lastname: Salminen
authors.affiliation: Division of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden. Electronic address: Goran.Karlsson@med.lu.se.
authors.forename: Göran
authors.initials: G
authors.lastname: Karlsson
authors.affiliation: Stem Cell Group, University College London Cancer Institute, London, United Kingdom.
authors.forename: Tariq
authors.initials: T
authors.lastname: Enver
authors.affiliation: Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Karlsson
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics* / Q000378:metabolism; D050989:GATA2 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051901:Smad4 Protein / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D016212:Transforming Growth Factor beta