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Unfolded protein response suppresses CEBPA by induction of calreticulin in acute myeloid leukaemia
The unfolded protein response (UPR) is triggered by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). The role of the UPR during leukemogenesis is unknown so far. Here, we studied the induction of mediators of the UPR in leukaemic cells of AML patients. Increased expressi...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829017/ https://www.ncbi.nlm.nih.gov/pubmed/19659458 http://dx.doi.org/10.1111/j.1582-4934.2009.00870.x |
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author | Schardt, Julian A Eyholzer, Marianne Timchenko, Nikolai A Mueller, Beatrice U Pabst, Thomas |
author_facet | Schardt, Julian A Eyholzer, Marianne Timchenko, Nikolai A Mueller, Beatrice U Pabst, Thomas |
author_sort | Schardt, Julian A |
collection | PubMed |
description | The unfolded protein response (UPR) is triggered by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). The role of the UPR during leukemogenesis is unknown so far. Here, we studied the induction of mediators of the UPR in leukaemic cells of AML patients. Increased expression of the spliced variant of the X-box binding protein 1 (XBP1s) was detected in 17.4% (16 of 92) of AML patients. Consistent with activated UPR, this group also had increased expression of ER-resident chaperones such as the 78 kD glucose-regulated protein (GRP78) and of calreticulin. Conditional expression of calreticulin in leukaemic U937 cells was found to increase calreticulin binding to the CEBPA mRNA thereby efficiently blocking translation of the myeloid key transcription factor CEBPA and ultimately affecting myeloid differentiation. Consequently, leukaemic cells from AML patients with activated UPR and thus increased calreticulin levels showed in fact suppressed CEBPA protein expression. We identified two functional ER stress response elements (ERSE) in the calreticulin promoter. The presence of NFY and ATF6, as well as an intact binding site for YY1 within these ERSE motifs were essential for mediating sensitivity to ER stress and activation of calreticulin. Thus, we propose a model of the UPR being activated in a considerable subset of AML patients through induction of calreticulin along the ATF6 pathway, thereby ultimately suppressing CEBPA translation and contributing to the block in myeloid differentiation. |
format | Online Article Text |
id | pubmed-3829017 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-38290172015-04-20 Unfolded protein response suppresses CEBPA by induction of calreticulin in acute myeloid leukaemia Schardt, Julian A Eyholzer, Marianne Timchenko, Nikolai A Mueller, Beatrice U Pabst, Thomas J Cell Mol Med Original Articles The unfolded protein response (UPR) is triggered by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). The role of the UPR during leukemogenesis is unknown so far. Here, we studied the induction of mediators of the UPR in leukaemic cells of AML patients. Increased expression of the spliced variant of the X-box binding protein 1 (XBP1s) was detected in 17.4% (16 of 92) of AML patients. Consistent with activated UPR, this group also had increased expression of ER-resident chaperones such as the 78 kD glucose-regulated protein (GRP78) and of calreticulin. Conditional expression of calreticulin in leukaemic U937 cells was found to increase calreticulin binding to the CEBPA mRNA thereby efficiently blocking translation of the myeloid key transcription factor CEBPA and ultimately affecting myeloid differentiation. Consequently, leukaemic cells from AML patients with activated UPR and thus increased calreticulin levels showed in fact suppressed CEBPA protein expression. We identified two functional ER stress response elements (ERSE) in the calreticulin promoter. The presence of NFY and ATF6, as well as an intact binding site for YY1 within these ERSE motifs were essential for mediating sensitivity to ER stress and activation of calreticulin. Thus, we propose a model of the UPR being activated in a considerable subset of AML patients through induction of calreticulin along the ATF6 pathway, thereby ultimately suppressing CEBPA translation and contributing to the block in myeloid differentiation. Blackwell Publishing Ltd 2010-06 2009-07-31 /pmc/articles/PMC3829017/ /pubmed/19659458 http://dx.doi.org/10.1111/j.1582-4934.2009.00870.x Text en © 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd |
spellingShingle | Original Articles Schardt, Julian A Eyholzer, Marianne Timchenko, Nikolai A Mueller, Beatrice U Pabst, Thomas Unfolded protein response suppresses CEBPA by induction of calreticulin in acute myeloid leukaemia |
title | Unfolded protein response suppresses CEBPA by induction of calreticulin in acute myeloid leukaemia |
title_full | Unfolded protein response suppresses CEBPA by induction of calreticulin in acute myeloid leukaemia |
title_fullStr | Unfolded protein response suppresses CEBPA by induction of calreticulin in acute myeloid leukaemia |
title_full_unstemmed | Unfolded protein response suppresses CEBPA by induction of calreticulin in acute myeloid leukaemia |
title_short | Unfolded protein response suppresses CEBPA by induction of calreticulin in acute myeloid leukaemia |
title_sort | unfolded protein response suppresses cebpa by induction of calreticulin in acute myeloid leukaemia |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829017/ https://www.ncbi.nlm.nih.gov/pubmed/19659458 http://dx.doi.org/10.1111/j.1582-4934.2009.00870.x |
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