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.
Highlights
During cancer progression, tumor cells are exposed to physiological stresses, such as hypoxia and nutrient limitation, either as a result of aberrant proliferation or chemotherapy intervention [1]
We applied a range of compounds to induce Activating Transcription Factor 4 (ATF4)-mediated cellular stress responses and found the Btg1 mRNA to be upregulated in mouse embryonic fibroblasts (MEFs) in response to these stressors (Figure 1A)
B-cell Translocation Gene 1 (BTG1) mRNA is downregulated in several solid tumors, including thyroid, lung, nasopharyngeal and breast cancer, while decreased expression is correlated with poor overall survival or increased cellular invasion [30,31,32,33,34]
Summary
Tumor cells are exposed to physiological stresses, such as hypoxia and nutrient limitation, either as a result of aberrant proliferation or chemotherapy intervention [1]. The phosphorylation events mediated by these kinases repress global protein synthesis but paradoxically increase the translation of a subset of mRNAs, including that of ATF4 [2, 3, 9] This member of the basic-region leucine zipper (bZIP) transcription factor family both directly and indirectly promotes the expression of hundreds of genes involved in metabolism, protein synthesis and nutrient homeostasis. ATF4-mediated stress responses govern metabolic and oxidative adaptation in various cell types such as neurons, osteoblasts, hepatocytes and hematopoietic stem cells [6, 11,12,13] This pathway is deregulated in a variety of cancers, including fibrosarcoma, neuroblastoma, multiple myeloma and breast cancer, which allows cancer cells to sustain growth under unfavorable circumstances [14,15,16,17]
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