A1 Refereed original research article in a scientific journal
Arginine methylation of the p30 C/EBPα oncoprotein regulates progenitor proliferation and myeloid differentiation
Authors: Nguyen, Linh T.; Zimmermann, Karin; Kowenz-Leutz, Elisabeth; Dörr, Dorothea; Schütz, Anja; Schönheit, Jörg; Mildner, Alexander; Leutz, Achim
Publisher: Cell Press
Publication year: 2024
Journal: iScience
Journal name in source: iScience
Article number: 111199
Volume: 27
Issue: 11
eISSN: 2589-0042
DOI: https://doi.org/10.1016/j.isci.2024.111199
Web address : https://doi.org/10.1016/j.isci.2024.111199
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/459205997
The transcription factor CCAAT enhancer binding protein alpha (C/EBPα) is a master regulator of myelopoiesis. CEBPA encodes a long (p42) and a truncated (p30) protein isoform from a single mRNA. Mutations that abnormally enhance expression of p30 are associated with acute myelogenous leukemia (AML). We show by mutational analysis that three highly conserved arginine residues in the p30 C/EBPα N-terminus, previously found to be methylated, are involved in myeloid lineage commitment, progenitor proliferation, and differentiation. The conservative amino acid substitution with lysine that retains the amino acid side chain charge enhanced progenitor proliferation, while a non-conservative substitution with uncharged side chains (alanine, leucine) impaired proliferation and enhanced granulopoiesis. Analysis of protein interactions suggested that arginine methylation of p30 C/EBPα differentially determines interactions with SWI/SNF and MLL complexes. Pharmacological targeting of p30 C/EBPα arginine methylation may have clinical relevance in myeloproliferative and inflammatory diseases, in neutropenia, and in leukemic stem cells.
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