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PMID: 11340171 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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

Molecular and cellular biology ·Vol. 21 ·No. 11 ·2001-06-00 ·Pages 3789-806

Johansen LM, Iwama A, Lodie TA, Sasaki K, Felsher DW, Golub TR, Tenen DG

Abstract

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.

MeSH Terms
Animals Binding Sites CCAAT-Enhancer-Binding Protein-alpha/genetics,metabolism COS Cells Carrier Proteins Cell Cycle Proteins Cell Differentiation Cell Line Chlorocebus aethiops DNA-Binding Proteins E2F Transcription Factors Gene Expression Regulation Granulocytes/cytology Humans Neutrophils/cytology Promoter Regions, Genetic Proto-Oncogene Proteins c-myc/genetics Retinoblastoma-Binding Protein 1 Transcription Factor DP1 Transcription Factors/metabolism Tumor Cells, Cultured U937 Cells
Chemicals
Arid4a protein, mouse CCAAT-Enhancer-Binding Protein-alpha Carrier Proteins Cell Cycle Proteins DNA-Binding Proteins E2F Transcription Factors Proto-Oncogene Proteins c-myc Retinoblastoma-Binding Protein 1 Transcription Factor DP1 Transcription Factors
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Johansen L M
Harvard Institutes of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
Iwama A
Lodie T A
Sasaki K
Felsher D W
Golub T R
Tenen D G
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.21.11.3789-3806.2001
Published
2001-06-00
Pages
3789-806
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC87031
Subset
IM
Grants
NIDDK NIH HHS · F32 DK009892 · United States
NHLBI NIH HHS · R01 HL056745 · United States
NIDDK NIH HHS · F32DK09892 · United States
NHLBI NIH HHS · HL56745 · United States
External Links
PubMed source DOI: 10.1128/MCB.21.11.3789-3806.2001 PMC Full Text View journal details
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