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Molecular and Cellular Biology, June 2001, p. 3789-3806, Vol. 21, No. 11
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.11.3789-3806.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

c-Myc Is a Critical Target for C/EBPalpha in Granulopoiesis

Lisa M. Johansen,1 Atsushi Iwama,2 Tracey A. Lodie,1 Koichi Sasaki,3 Dean W. Felsher,4 Todd R. Golub,3 and Daniel G. Tenen1,*

Harvard Institutes of Medicine1 and Dana-Farber Cancer Institute,3 Harvard Medical School, Boston, Massachusetts 02115; Department of Immunology, University of Tsukuba, Tsukuba, Japan2; and Stanford University School of Medicine, Stanford, California 04305-51154

Received 6 October 2000/Returned for modification 22 November 2000/Accepted 14 March 2001

CCAAT/enhancer binding protein alpha  (C/EBPalpha ) is an integral factor in the granulocytic developmental pathway, as myeloblasts from C/EBPalpha -null mice exhibit an early block in differentiation. Since mice deficient for known C/EBPalpha target genes do not exhibit the same block in granulocyte maturation, we sought to identify additional C/EBPalpha target genes essential for myeloid cell development. To identify such genes, we used both representational difference analysis and oligonucleotide array analysis with RNA derived from a C/EBPalpha -inducible myeloid cell line. From each of these independent screens, we identified c-Myc as a C/EBPalpha negatively regulated gene. We mapped an E2F binding site in the c-Myc promoter as the cis-acting element critical for C/EBPalpha negative regulation. The identification of c-Myc as a C/EBPalpha target gene is intriguing, as it has been previously shown that down-regulation of c-Myc can induce myeloid differentiation. Here we show that stable expression of c-Myc from an exogenous promoter not responsive to C/EBPalpha -mediated down-regulation forces myeloblasts to remain in an undifferentiated state. Therefore, C/EBPalpha negative regulation of c-Myc is critical for allowing early myeloid precursors to enter a differentiation pathway. This is the first report to demonstrate that C/EBPalpha directly affects the level of c-Myc expression and, thus, the decision of myeloid blasts to enter into the granulocytic differentiation pathway.

* Corresponding author. Mailing address: Harvard Institutes of Medicine, Room 954, 77 Ave. Louis Pasteur, Boston, MA 02115. Phone: (617) 667-5561. Fax: (617) 667-3299. E-mail: dtenen{at}caregroup.harvard.edu.

Molecular and Cellular Biology, June 2001, p. 3789-3806, Vol. 21, No. 11
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.11.3789-3806.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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