title: Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels.
abstract: The transcription factor far upstream element binding protein (FBP) binds and activates the MYC promoter when far upstream element is via TFIIH helicase activity early in the transcription cycle. The fundamental biology and pathology of FBP are complex. In some tumors FBP seems pro-oncogenic, whereas in others it is a tumor suppressor. We generated an FBP knockout (Fubp1(-/-)) mouse to study FBP deficiency. FBP is embryo lethal from embryonic day 10.5 to birth. A spectrum of pathology is associated with FBP loss; besides cerebral hyperplasia and pulmonary hypoplasia, pale livers, hypoplastic spleen, thymus, and bone marrow, cardiac hypertrophy, placental distress, and small size were all indicative of anemia. Immunophenotyping of hematopoietic cells in wild-type versus knockout livers revealed irregular trilineage anemia, with deficits in colony formation. Despite normal numbers of hematopoietic stem cells, transplantation of Fubp1(-/-) hematopoietic stem cells into irradiated mice entirely failed to reconstitute hematopoiesis. In competitive transplantation assays against wild-type donor bone marrow, Fubp1(-/-) hematopoietic stem cells functioned only sporadically at a low level. Although cultures of wild-type mouse embryo fibroblasts set Myc levels precisely, Myc levels of mouse varied wildly between fibroblasts harvested from different Fubp1(-/-) embryos, suggesting that FBP contributes to Myc set point fixation. FBP helps to hold multiple physiologic processes to close tolerances, at least in part by constraining Myc expression.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Weixin
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Laboratory of Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Yang Jo
authors.initials: YJ
authors.lastname: Chung
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Edgardo R
authors.initials: ER
authors.lastname: Parrilla Castellar
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Chung
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Russell
authors.initials: R
authors.lastname: Bandle
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Juhong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Mouse Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland.
authors.forename: Lino
authors.initials: L
authors.lastname: Tessarollo
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Eric
authors.initials: E
authors.lastname: Batchelor
authors.affiliation: Laboratory of Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Aplan
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Electronic address: levens@helix.nih.gov.
authors.forename: David
authors.initials: D
authors.lastname: Levens
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D047108:Embryonic Development / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C118921:Fubp protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc