Phosphorylation of C/EBPα inhibits granulopoiesis

SE Ross, HS Radomska, B Wu, P Zhang… - … and cellular biology, 2004 - Taylor & Francis
SE Ross, HS Radomska, B Wu, P Zhang, JN Winnay, L Bajnok, WS Wright, F Schaufele…
Molecular and cellular biology, 2004Taylor & Francis
CCAAT/enhancer-binding protein α (C/EBPα) 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 …
CCAAT/enhancer-binding protein α (C/EBPα) 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.
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