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.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Ross SE,Radomska HS,Wu B,Zhang P,Winnay JN,Bajnok L,Wright WS,Schaufele F,Tenen DG,MacDougald OAdoi
10.1128/mcb.24.2.675-686.2004subject
Has Abstractpub_date
2004-01-01 00:00:00pages
675-86issue
2eissn
0270-7306issn
1098-5549journal_volume
24pub_type
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