Protein disulfide isomerase blocks CEBPA translation and is up-regulated during the unfolded protein response in AML

Haefliger, Simon; Klebig, Christiane; Schaubitzer, Kerstin; Schardt, Julian; Timchenko, Nikolai; Mueller, Beatrice U; Pabst, Thomas (2011). Protein disulfide isomerase blocks CEBPA translation and is up-regulated during the unfolded protein response in AML. Blood, 117(22), pp. 5931-40. Washington, D.C.: American Society of Hematology 10.1182/blood-2010-08-304485

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Deregulation of the myeloid key transcription factor CEBPA is a common event in acute myeloid leukemia (AML). We previously reported that the chaperone calreticulin is activated in subgroups of AML patients and that calreticulin binds to the stem loop region of the CEBPA mRNA, thereby blocking CEBPA translation. In this study, we screened for additional CEBPA mRNA binding proteins and we identified protein disulfide isomerase (PDI), an endoplasmic reticulum (ER) resident protein, to bind to the CEBPA mRNA stem loop region. We found that forced PDI expression in myeloid leukemic cells in fact blocked CEBPA translation, but not transcription, whereas abolishing PDI function restored CEBPA protein. In addition, PDI protein displayed direct physical interaction with calreticulin. Induction of ER stress in leukemic HL60 and U937 cells activated PDI expression, thereby decreasing CEBPA protein levels. Finally, leukemic cells from 25.4% of all AML patients displayed activation of the unfolded protein response as a marker for ER stress, and these patients also expressed significantly higher PDI levels. Our results indicate a novel role of PDI as a member of the ER stress-associated complex mediating blocked CEBPA translation and thereby suppressing myeloid differentiation in AML patients with activated unfolded protein response (UPR).

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology
UniBE Contributor:	Pabst, Thomas Niklaus
ISSN:	0006-4971
Publisher:	American Society of Hematology
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:20
Last Modified:	02 Mar 2023 23:20
Publisher DOI:	10.1182/blood-2010-08-304485
PubMed ID:	21471526
Web of Science ID:	000291203200021
URI:	https://boris.unibe.ch/id/eprint/6465 (FactScience: 211431)