C/EBPαp30, a myeloid leukemia oncoprotein, limits G-CSF receptor expression but not terminal granulopoiesis via site-selective inhibition of C/EBP DNa binding

Rebecca Cleaves, Qian Fei Wang, Alan D. Friedman

Research output: Contribution to journalArticle

Abstract

Heterozygous mutations of the CEBPA gene are present in 5% of acute myeloid leukemia (AML) cases and often lead to the expression of an N-terminally truncated, 30 kDa isoform, C/EBPαp30, from an internal translation start site. We have assessed the effect of C/EBPαp30 on granulopoiesis utilizing C/EBPαp30-ER, containing the estradiol receptor ligand-binding domain. In contrast to C/EBPα-ER, C/EBPαp30-ER did not induce 32Dcl3 myeloid cell differentiation in IL-3. However, both isoforms, when expressed at high levels, were capable of inhibiting E2F activity in 32Dcl3 cells and of slowing their G1 to S progression. C/EBPαp30 repressed expression of the endogenous G-CSF receptor several-fold. To facilitate investigation of the effect of C/EBPαp30-ER on granulopoiesis downstream of G-CSF signalling, we coexpressed exogenous G-CSF receptor. C/EBPαp30-ER/GR cells expressed several granulocytic markers in G-CSF and demonstrated nuclear maturation. Rat C/EBPα-ER and C/EBPαp30-ER, expressed in 293T cells, bound the C/EBP site from the NE gene with similar affinity, as did human C/EBPα and C/EBPαp30. In contrast, C/ EBPαp30 bound the C/EBP sites in the PU.1 or GR gene with 3-6-fold reduced affinity. Thus, the selective inhibition of GR expression by C/EBPαp30-ER is due in part to its variable affinity for C/EBP sites. Variation in affinity for selected cis elements among isoforms may affect the biology of basic region-leucine zipper (bZIP) proteins.

Original languageEnglish (US)
Pages (from-to)716-725
Number of pages10
JournalOncogene
Volume23
Issue number3
DOIs
StatePublished - Jan 22 2004

Keywords

  • AML
  • C/EBPα
  • Cell cycle
  • Differentiation
  • Leukemia

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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