title: Phosphorylation of C/EBPalpha inhibits granulopoiesis.
abstract: CCAAT/enhancer-binding protein alpha (C/EBPalpha) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes. Although C/EBPalpha is known to induce granulopoiesis while suppressing monocyte differentiation, it is unclear how C/EBPalpha regulates this cell fate choice at the mechanistic level. Here we report that inducers of monocyte differentiation inhibit the alternate cell fate choice, that of granulopoiesis, through inhibition of C/EBPalpha. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (ERK1/2), which interact with C/EBPalpha through an FXFP docking site and phosphorylate serine 21. As a consequence of C/EBPalpha phosphorylation, induction of granulocyte differentiation by C/EBPalpha or retinoic acid is inhibited. Our analysis of C/EBPalpha by fluorescent resonance energy transfer revealed that phosphorylation induces conformational changes in C/EBPalpha, increasing the distance between the amino termini of C/EBPalpha dimers. Thus, myeloid development is partly regulated by an ERK1/2-mediated change in the conformation of C/EBPalpha that favors monocyte differentiation by blocking granulopoiesis.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, 1301 E. Catherine Street, Ann Arbor, MI 48109-0622, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Ross
authors.forename: Hanna S
authors.initials: HS
authors.lastname: Radomska
authors.forename: Bo
authors.initials: B
authors.lastname: Wu
authors.forename: Pu
authors.initials: P
authors.lastname: Zhang
authors.forename: Jonathon N
authors.initials: JN
authors.lastname: Winnay
authors.forename: Laszlo
authors.initials: L
authors.lastname: Bajnok
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Wright
authors.forename: Fred
authors.initials: F
authors.lastname: Schaufele
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Ormond A
authors.initials: OA
authors.lastname: MacDougald
mesh_terms: D041721:3T3-L1 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D006098:Granulocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D019891:Leukopoiesis / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D012694:Serine / Q000737:chemistry; D014212:Tretinoin / Q000494:pharmacology; D020298:U937 Cells
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D012694:Serine; D014212:Tretinoin