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Molecular and Cellular Biology DOI:

c-Myc is a critical target for c/EBPalpha in granulopoiesis

Publication TypeJournal Article
Year of Publication2001
AuthorsJohansen, LM, Iwama, A, Lodie, TA, Sasaki, K, Felsher, DW, Golub, TR, Tenen, DG
JournalMolecular and Cellular Biology
Pages3789 - 806
Date Published2001/06//
ISBN Number0270-7306
KeywordsAnimals, Binding Sites, Cancer, Carrier Proteins, CCAAT-Enhancer-Binding Protein-alpha, Cell Cycle Proteins, Cell Differentiation, Cell Line, Cercopithecus aethiops, COS Cells, DNA-Binding Proteins, E2F Transcription Factors, Gene Expression Regulation, Granulocy

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.