Ras signaling enhances the activity of C/EBPα to induce granulocytic differentiation by phosphorylation of serine 248

Gerhard Behre, Sheo M. Singh, Huaitian Liu, Laura T. Bortolin, Max Christopeit, Hanna S. Radomska, Janki Rangatia, Wolfgang Hiddemann, Alan D. Friedman, Daniel G. Tenen

Research output: Contribution to journalArticlepeer-review

Abstract

The transcription factor C/EBPα regulates early steps of normal granulocyte differentiation since mice with a disruption of the C/EBPα gene do not express detectable levels of the granulocyte colony-stimulating factor receptor and produce no neutrophils. We have recently shown that C/EBPα function is also impaired in acute myeloid leukemias. However, how the transcriptional activity of C/EBPα is regulated both in myelopoiesis and leukemogenesis is not fully understood. The current study demonstrates that activated Ras enhances the ability of C/EBPα to transactivate the granulocyte colony-stimulating factor receptor promoter and a minimal promoter containing only C/EBP DNA binding sites. Ras signaling activates C/EBPα via the transactivation domain because it enhances the transactivation function of a fusion protein containing a Ga14 DNA binding domain and the C/EBPα transactivation domain and does not change C/EBPα DNA binding. Ras acts on serine 248 of the C/EBPα transactivation domain, because it does not enhance the transactivation function of a C/EBPα serine 248 to alanine point mutant. Interestingly, serine 248 of C/EBPα is a protein kinase C (PKC) consensus site, and a PKC inhibitor blocks the activation of C/EBPα by Ras. Ras signaling leads to phosphorylation of C/EBPα in vivo. Finally, mutation of serine 248 to alanine obviates the ability of C/EBPα to induce granulocytic differentiation. These data suggest a model where Ras signaling enhances the activity of C/EBPα to induce granulocytic differentiation by phosphorylation of serine 248.

Original languageEnglish (US)
Pages (from-to)26293-26299
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number29
DOIs
StatePublished - Jul 19 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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