Research Papers:

Tumor suppressor BTG1 promotes PRMT1-mediated ATF4 function in response to cellular stress

Laurensia Yuniati, Laurens T. van der Meer, Esther Tijchon, Dorette van Ingen Schenau, Liesbeth van Emst, Marloes Levers, Sander A.L. Palit, Caroline Rodenbach, Geert Poelmans, Peter M. Hoogerbrugge, Jixiu Shan, Michael S. Kilberg, Blanca Scheijen and Frank N. van Leeuwen _

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Oncotarget. 2016; 7:3128-3143. https://doi.org/10.18632/oncotarget.6519

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Laurensia Yuniati1,*, Laurens T. van der Meer1,*, Esther Tijchon1, Dorette van Ingen Schenau1, Liesbeth van Emst1, Marloes Levers1, Sander A.L. Palit1, Caroline Rodenbach1, Geert Poelmans2,3,4, Peter M. Hoogerbrugge1,5, Jixiu Shan6, Michael S. Kilberg6, Blanca Scheijen1, Frank N. van Leeuwen1

1Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands

2Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

3Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands

4Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands

5Prinses Maxima Center for Pediatric Oncology, De Bilt, The Netherlands

6Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL, USA

*These authors contributed equally to this work

Correspondence to:

Frank N. van Leeuwen, e-mail: [email protected]

Keywords: BTG1, leukemia, ATF4, cellular stress, PRMT1

Received: May 25, 2015     Accepted: November 19, 2015     Published: December 09, 2015


Cancer cells are frequently exposed to physiological stress conditions such as hypoxia and nutrient limitation. Escape from stress-induced apoptosis is one of the mechanisms used by malignant cells to survive unfavorable conditions. B-cell Translocation Gene 1 (BTG1) is a tumor suppressor that is frequently deleted in acute lymphoblastic leukemia and recurrently mutated in diffuse large B cell lymphoma. Moreover, low BTG1 expression levels have been linked to poor outcome in several solid tumors. How loss of BTG1 function contributes to tumor progression is not well understood. Here, using Btg1 knockout mice, we demonstrate that loss of Btg1 provides a survival advantage to primary mouse embryonic fibroblasts (MEFs) under stress conditions. This pro-survival effect involves regulation of Activating Transcription Factor 4 (ATF4), a key mediator of cellular stress responses. We show that BTG1 interacts with ATF4 and positively modulates its activity by recruiting the protein arginine methyl transferase PRMT1 to methylate ATF4 on arginine residue 239. We further extend these findings to B-cell progenitors, by showing that loss of Btg1 expression enhances stress adaptation of mouse bone marrow-derived B cell progenitors. In conclusion, we have identified the BTG1/PRMT1 complex as a new modifier of ATF4 mediated stress responses.

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