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 language | English (US) |
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Pages (from-to) | 26293-26299 |
Number of pages | 7 |
Journal | Journal of Biological Chemistry |
Volume | 277 |
Issue number | 29 |
DOIs | |
State | Published - Jul 19 2002 |
Externally published | Yes |
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology