Far upstream element binding protein plays a crucial role in embryonic development, hematopoiesis, and stabilizing myc expression levels

Weixin Zhou, Yang Jo Chung, Edgardo R. Parrilla Castellar, Ying Zheng, Hye Jung Chung, Russell Bandle, Juhong Liu, Lino Tessarollo, Eric Batchelor, Peter D. Aplan, David Levens

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)701-715
Number of pages15
JournalAmerican Journal of Pathology
Volume186
Issue number3
DOIs
StatePublished - Mar 1 2016

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