Erythropoietin signaling regulates heme biosynthesis.

Autor:	Chung J; Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States., Wittig JG; Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States., Ghamari A; Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, United States., Maeda M; Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States., Dailey TA; Department of Microbiology, University of Georgia, Athens, United States.; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, United States., Bergonia H; Division of Hematology and Hematologic Malignancies, University of Utah School of Medicine, Salt Lake City, United States., Kafina MD; Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States., Coughlin EE; Genome Center of Wisconsin, Madison, United States., Minogue CE; Department of Chemistry, University of Wisconsin-Madison, Madison, United States., Hebert AS; Genome Center of Wisconsin, Madison, United States., Li L; Department of Pathology, University of Utah School of Medicine, Salt Lake City, United States., Kaplan J; Department of Pathology, University of Utah School of Medicine, Salt Lake City, United States., Lodish HF; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, United States., Bauer DE; Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, United States.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States., Orkin SH; Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, United States.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States., Cantor AB; Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, United States.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States., Maeda T; Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States., Phillips JD; Division of Hematology and Hematologic Malignancies, University of Utah School of Medicine, Salt Lake City, United States., Coon JJ; Genome Center of Wisconsin, Madison, United States.; Department of Chemistry, University of Wisconsin-Madison, Madison, United States.; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, United States., Pagliarini DJ; Department of Biochemistry, University of Wisconsin-Madison, Madison, United States., Dailey HA; Department of Microbiology, University of Georgia, Athens, United States.; Department of Biochemistry and Molecular Biology, University of Georgia, Athens, United States., Paw BH; Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.; Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, United States.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2017 May 29; Vol. 6. Date of Electronic Publication: 2017 May 29.
DOI:	10.7554/eLife.24767
Abstrakt:	Heme is required for survival of all cells, and in most eukaryotes, is produced through a series of eight enzymatic reactions. Although heme production is critical for many cellular processes, how it is coupled to cellular differentiation is unknown. Here, using zebrafish, murine, and human models, we show that erythropoietin (EPO) signaling, together with the GATA1 transcriptional target, AKAP10 , regulates heme biosynthesis during erythropoiesis at the outer mitochondrial membrane. This integrated pathway culminates with the direct phosphorylation of the crucial heme biosynthetic enzyme, ferrochelatase (FECH) by protein kinase A (PKA). Biochemical, pharmacological, and genetic inhibition of this signaling pathway result in a block in hemoglobin production and concomitant intracellular accumulation of protoporphyrin intermediates. Broadly, our results implicate aberrant PKA signaling in the pathogenesis of hematologic diseases. We propose a unifying model in which the erythroid transcriptional program works in concert with post-translational mechanisms to regulate heme metabolism during normal development.
Databáze:	MEDLINE
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