title: Tumor suppressor BTG1 promotes PRMT1-mediated ATF4 function in response to cellular stress.
abstract: 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.
authors.affiliation: Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Laurensia
authors.initials: L
authors.lastname: Yuniati
authors.affiliation: Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Laurens T
authors.initials: LT
authors.lastname: van der Meer
authors.affiliation: Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Tijchon
authors.affiliation: Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Dorette
authors.initials: D
authors.lastname: van Ingen Schenau
authors.affiliation: Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: van Emst
authors.affiliation: Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marloes
authors.initials: M
authors.lastname: Levers
authors.affiliation: Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Sander A L
authors.initials: SA
authors.lastname: Palit
authors.affiliation: Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Caroline
authors.initials: C
authors.lastname: Rodenbach
authors.affiliation: Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
authors.forename: Geert
authors.initials: G
authors.lastname: Poelmans
authors.affiliation: Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands.|Prinses Maxima Center for Pediatric Oncology, De Bilt, The Netherlands.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Hoogerbrugge
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Jixiu
authors.initials: J
authors.lastname: Shan
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kilberg
authors.affiliation: Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Blanca
authors.initials: B
authors.lastname: Scheijen
authors.affiliation: Laboratory of Pediatric Oncology, Radboud Institute for Molecular Life Science, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Frank N
authors.initials: FN
authors.lastname: van Leeuwen
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001402:B-Lymphocytes / Q000166:cytology; D045744:Cell Line, Tumor; D005347:Fibroblasts; D006801:Humans; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology*; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: C497109:ATF4 protein, human; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D051701:Activating Transcription Factor 4; C074086:BTG1 protein, human; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases
keywords: ATF4; BTG1; PRMT1; cellular stress; leukemia