Elevated c-Jun expression in acute myeloid leukemias inhibits C/EBPalpha DNA binding via leucine zipper domain interaction

Oncogene. 2003 Jul 24;22(30):4760-4. doi: 10.1038/sj.onc.1206664.


Transcription factor C/EBPalpha induces normal myeloid differentiation, inactivation of C/EBPalpha leads to a differentiation block in acute myeloid leukemias (AML), and overexpression of C/EBPalpha results in AML growth arrest and differentiation. Recent reports suggest that C/EBPalpha is activated or inactivated via protein-protein interactions. We previously reported that C/EBPalpha needs to inactivate the proto-oncogene c-Jun via leucine zipper domain interaction in order to induce granulocytic differentiation. We, therefore, hypothesized that c-Jun expression might be elevated in AML and subsequently inactivate C/EBPalpha. In fact, compared to normal bone marrow mononuclear cells, c-Jun expression is increased in AML patient samples (Affymetrix expression microarray analysis, n=166). c-Jun binds to C/EBPalpha via the leucine zipper domains and prevents C/EBPalpha from DNA binding. Inactivation of C/EBPalpha by c-Jun is necessary for c-Jun to induce proliferation because c-Jun-induced proliferation can be prevented by ectopic overexpression of C/EBPalpha. The dominant-negative 30-kDa C/EBPalpha protein, found in AML, fails to downregulate c-Jun mRNA expression in AML patient samples. Thus, our data suggest a model for AML in which c-Jun promotes proliferation and prevents differentiation by inhibiting C/EBPalpha DNA binding via leucine zipper domain interaction. It might depend on the expression levels of C/EBPalpha and c-Jun, if inhibition of C/EBPalpha by c-Jun or if inhibition of c-Jun by C/EBPalpha is more predominant: proliferation versus differentiation; AML versus normal myeloid development.

MeSH terms

  • CCAAT-Enhancer-Binding Protein-alpha / antagonists & inhibitors*
  • Cell Differentiation
  • Cell Division
  • DNA / metabolism*
  • Down-Regulation
  • Flow Cytometry
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Leucine Zippers
  • Leukemia, Myeloid, Acute / enzymology*
  • Leukemia, Myeloid, Acute / metabolism
  • Mitogen-Activated Protein Kinases / biosynthesis*
  • Mitogen-Activated Protein Kinases / chemistry
  • Models, Molecular
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Mas
  • RNA, Messenger / metabolism
  • Tumor Cells, Cultured


  • CCAAT-Enhancer-Binding Protein-alpha
  • MAS1 protein, human
  • Proto-Oncogene Mas
  • RNA, Messenger
  • DNA
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases