Phosphorylation of C/EBPα Inhibits Granulopoiesis

Sarah E. Ross, Hanna S. Radomska, Bo Wu, Pu Zhang, Jonathon N. Winnay, Laszlo Bajnok, Wendy S. Wright, Fred Schaufele, Daniel G. Tenen, Ormond A. MacDougald

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Abstract

CCAAT/enhancer-binding protein α (C/EBP(α) is one of the key transcription factors that mediate lineage specification and differentiation of multipotent myeloid progenitors into mature granulocytes. Although C/EBPα is known to induce granulopoiesis while suppressing monocyte differentiation, it is unclear how C/EBPα 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/EBPα. This inhibition is mediated by extracellular signal-regulated kinases 1 and/or 2 (ERK1/2), which interact with C/EBPα through an FXFP docking site and phosphorylate serine 21. As a consequence of C/EBPα phosphorylation, induction of granulocyte differentiation by C/EBPα or retinoic acid is inhibited. Our analysis of C/EBPα by fluorescent resonance energy transfer revealed that phosphorylation induces conformational changes in C/EBPα, increasing the distance between the amino termini of C/EBPα dimers. Thus, myeloid development is partly regulated by an ERK1/2-mediated change in the conformation of C/EBPα that favors monocyte differentiation by blocking granulopoiesis.

Original languageEnglish
Pages (from-to)675-686
Number of pages12
JournalMolecular and cellular biology
Volume24
Issue number2
DOIs
Publication statusPublished - Jan 1 2004

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Ross, S. E., Radomska, H. S., Wu, B., Zhang, P., Winnay, J. N., Bajnok, L., Wright, W. S., Schaufele, F., Tenen, D. G., & MacDougald, O. A. (2004). Phosphorylation of C/EBPα Inhibits Granulopoiesis. Molecular and cellular biology, 24(2), 675-686. https://doi.org/10.1128/MCB.24.2.675-686.2004