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

Oncogene volume 23, pages 716–725 (2004)Cite this article

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.

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Acknowledgements

We thank D Tenen, B Porse, and C Nerlov for plasmids and C Stocking for her comparison of rat, mouse, and human C/EBPα sequences. This work was supported by NIH Grant R01 HL51388. ADF is also supported by the Children's Cancer Foundation and is a Scholar of the Leukemia & Lymphoma Society.

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  1. Qian-fei Wang

    Present address: Genome Science Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA, 94720, USA

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  1. Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, 21231, MD, USA

    Rebecca Cleaves, Qian-fei Wang & Alan D Friedman

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Correspondence to Alan D Friedman.

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Cleaves, R., Wang, Qf. & Friedman, A. C/EBPαp30, a myeloid leukemia oncoprotein, limits G-CSF receptor expression but not terminal granulopoiesis via site-selective inhibition of C/EBP DNA binding. Oncogene 23, 716–725 (2004). https://doi.org/10.1038/sj.onc.1207172

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