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Molecular and Cellular Biology, January 2004, p. 675-686, Vol. 24, No. 2
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.2.675-686.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Phosphorylation of C/EBP{alpha} Inhibits Granulopoiesis

Sarah E. Ross,1,{dagger} Hanna S. Radomska,2,{dagger} Bo Wu,3 Pu Zhang,2 Jonathon N. Winnay,1 Laszlo Bajnok,1 Wendy S. Wright,1 Fred Schaufele,3 Daniel G. Tenen,2 and Ormond A. MacDougald1*

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan,1 Hematology/Oncology Division, Harvard Institutes of Medicine, Harvard Medical School, Boston, Massachusetts,2 Metabolic Research Unit, Diabetes Center and Department of Medicine, University of California, San Francisco, California3

Received 19 May 2003/ Returned for modification 16 July 2003/ Accepted 14 October 2003

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

* Corresponding author. Mailing address: Department of Molecular and Integrative Physiology, University of Michigan Medical School, 1301 E. Catherine St., Ann Arbor, MI 48109-0622. Phone: (734) 647-4880. Fax: (734) 936-8813. E-mail: macdouga{at}umich.edu.

{dagger} S. E. Ross and H. S. Radomska contributed equally to this work.

Molecular and Cellular Biology, January 2004, p. 675-686, Vol. 24, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.2.675-686.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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