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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2004-01

AUTHORS

Alan D Friedman, Qian-fei Wang, Rebecca Cleaves

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/EBPalphap30, from an internal translation start site. We have assessed the effect of C/EBPalphap30 on granulopoiesis utilizing C/EBPalphap30-ER, containing the estradiol receptor ligand-binding domain. In contrast to C/EBPalpha-ER, C/EBPalphap30-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/EBPalphap30 repressed expression of the endogenous G-CSF receptor several-fold. To facilitate investigation of the effect of C/EBPalphap30-ER on granulopoiesis downstream of G-CSF signalling, we coexpressed exogenous G-CSF receptor. C/EBPalphap30-ER/GR cells expressed several granulocytic markers in G-CSF and demonstrated nuclear maturation. Rat C/EBPalpha-ER and C/EBPalphap30-ER, expressed in 293T cells, bound the C/EBP site from the NE gene with similar affinity, as did human C/EBPalpha and C/EBPalphap30. In contrast, C/EBPalphap30 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/EBPalphap30-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. More... »

PAGES

716

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.onc.1207172

DOI

http://dx.doi.org/10.1038/sj.onc.1207172

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1024792163

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/14737106


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