Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression

An Author Correction to this article was published on 17 July 2019

This article has been updated


The c-Myc oncogene drives malignant progression and induces robust anabolic and proliferative programmes leading to intrinsic stress. The mechanisms enabling adaptation to MYC-induced stress are not fully understood. Here we reveal an essential role for activating transcription factor 4 (ATF4) in survival following MYC activation. MYC upregulates ATF4 by activating general control nonderepressible 2 (GCN2) kinase through uncharged transfer RNAs. Subsequently, ATF4 co-occupies promoter regions of over 30 MYC-target genes, primarily those regulating amino acid and protein synthesis, including eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), a negative regulator of translation. 4E-BP1 relieves MYC-induced proteotoxic stress and is essential to balance protein synthesis. 4E-BP1 activity is negatively regulated by mammalian target of rapamycin complex 1 (mTORC1)-dependent phosphorylation and inhibition of mTORC1 signalling rescues ATF4-deficient cells from MYC-induced endoplasmic reticulum stress. Acute deletion of ATF4 significantly delays MYC-driven tumour progression and increases survival in mouse models. Our results establish ATF4 as a cellular rheostat of MYC activity, which ensures that enhanced translation rates are compatible with survival and tumour progression.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Fig. 1: MYC-induced ATF4 inhibits apoptosis and promotes survival.
Fig. 2: The amino acid sensor GCN2 is activated by uncharged tRNAs and is required for optimal activation of ATF4 on MYC induction.
Fig. 3: ATF4 and MYC bind to common target genes.
Fig. 4: ATF4 suppresses mTORC1-dependent signalling and inhibition of mTORC1 reduces cell death of ATF4-deficient cells following MYC activation.
Fig. 5: Acute ablation of ATF4 significantly delays MYC-driven lymphomagenesis and promotes survival of MYC-driven lymphoma bearing mice.
Fig. 6: EIF4EBP1 positively correlates with ATF4-target gene expression and is associated with poor prognosis.

Data availability

tRNA microarray and ChIP–seq data that support the findings of this study have been deposited in the Gene Expression Omnibus under accession codes GSE116812 and GSE117240, respectively.

The human COAD, BRCA and SARC datasets were derived from the TCGA Data Hub on the University of California Santa Cruz Xena platform ( The dataset derived from this resource that supports the findings of this study is available in the following links. COAD:; BRCA:; SARC: The human DLBCL data were derived from the National Cancer Institute Center for Cancer Genomics website: The dataset derived from this resource that supports the findings of this study is available at

Statistics source data for graphical representations and statistical analyses in Figs. 16 and Supplementary Figs. 16 are provided in Supplementary Table 3. All other data supporting the findings of this study are available from the corresponding author on reasonable request.

Change history

  • 17 July 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.


  1. Pakos-Zebrucka, K. et al. The integrated stress response. EMBO Rep. 17, 1374–1395 (2016).

    Article  CAS  Google Scholar 

  2. Wek, R. C., Jiang, H. Y. & Anthony, T. G. Coping with stress: eIF2 kinases and translational control. Biochem. Soc. Trans. 34, 7–11 (2006).

    Article  CAS  Google Scholar 

  3. Dong, J., Qiu, H., Garcia-Barrio, M., Anderson, J. & Hinnebusch, A. G. Uncharged tRNA activates GCN2 by displacing the protein kinase moiety from a bipartite tRNA-binding domain. Mol. Cell 6, 269–279 (2000).

    Article  CAS  Google Scholar 

  4. Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, 619–633 (2003).

    Article  CAS  Google Scholar 

  5. Dey, S. et al. ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. J. Clin. Invest. 125, 2592–2608 (2015).

    Article  Google Scholar 

  6. Gardner, B. M., Pincus, D., Gotthardt, K., Gallagher, C. M. & Walter, P. Endoplasmic reticulum stress sensing in the unfolded protein response. Cold Spring Harb. Perspect. Biol. 5, a013169 (2013).

    Article  Google Scholar 

  7. Ye, J. et al. The GCN2–ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J. 29, 2082–2096 (2010).

    Article  CAS  Google Scholar 

  8. Bi, M. et al. ER stress-regulated translation increases tolerance to extreme hypoxia and promotes tumor growth. EMBO J. 24, 3470–3481 (2005).

    Article  CAS  Google Scholar 

  9. Fels, D. R. & Koumenis, C. The PERK/eIF2alpha/ATF4 module of the UPR in hypoxia resistance and tumor growth. Cancer Biol. Ther. 5, 723–728 (2006).

    Article  CAS  Google Scholar 

  10. Ozcan, U. et al. Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol. Cell 29, 541–551 (2008).

    Article  CAS  Google Scholar 

  11. Hart, L. S. et al. ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth. J. Clin. Invest. 122, 4621–4634 (2012).

    Article  CAS  Google Scholar 

  12. Tameire, F., Verginadis, I. I. & Koumenis, C. Cell intrinsic and extrinsic activators of the unfolded protein response in cancer: mechanisms and targets for therapy. Semin. Cancer Biol. 33, 3–15 (2015).

    Article  CAS  Google Scholar 

  13. Beroukhim, R. et al. The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).

    Article  CAS  Google Scholar 

  14. Iritani, B. M. & Eisenman, R. N. c-Myc enhances protein synthesis and cell size during B lymphocyte development. Proc. Natl Acad. Sci. USA 96, 13180–13185 (1999).

    Article  CAS  Google Scholar 

  15. Stine, Z. E., Walton, Z. E., Altman, B. J., Hsieh, A. L. & Dang, C. V. MYC, metabolism, and cancer. Cancer Discov. 5, 1024–1039 (2015).

    Article  CAS  Google Scholar 

  16. Barna, M. et al. Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature 456, 971–975 (2008).

    Article  CAS  Google Scholar 

  17. Lin, C. J. et al. Targeting synthetic lethal interactions between Myc and the eIF4F complex impedes tumorigenesis. Cell Rep. 1, 325–333 (2012).

    Article  CAS  Google Scholar 

  18. Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H. & Ron, D. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol. Cell 5, 897–904 (2000).

    Article  CAS  Google Scholar 

  19. Nagy, P., Varga, A., Pircs, K., Hegedus, K. & Juhasz, G. Myc-driven overgrowth requires unfolded protein response-mediated induction of autophagy and antioxidant responses in Drosophila melanogaster. PLoS Genet. 9, e1003664 (2013).

    Article  CAS  Google Scholar 

  20. Wang, Y. et al. Amino acid deprivation promotes tumor angiogenesis through the GCN2/ATF4 pathway. Neoplasia 15, 989–997 (2013).

    Article  Google Scholar 

  21. Sood, R., Porter, A. C., Olsen, D. A., Cavener, D. R. & Wek, R. C. A mammalian homologue of GCN2 protein kinase important for translational control by phosphorylation of eukaryotic initiation factor-2ɑ. Genetics 154, 787–801 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Gomez-Roman, N., Grandori, C., Eisenman, R. N. & White, R. J. Direct activation of RNA polymerase III transcription by c-Myc. Nature 421, 290–294 (2003).

    Article  CAS  Google Scholar 

  23. Wu, L. et al. Novel small-molecule inhibitors of RNA polymerase III. Eukaryot. Cell 2, 256–264 (2003).

    Article  CAS  Google Scholar 

  24. Avcilar-Kucukgoze, I. et al. Discharging tRNAs: a tug of war between translation and detoxification in Escherichia coli. Nucleic Acids Res. 44, 8324–8334 (2016).

    Article  CAS  Google Scholar 

  25. Han, J. et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell. Biol. 15, 481–490 (2013).

    Article  CAS  Google Scholar 

  26. Chen, H. et al. ATF4 regulates SREBP1c expression to control fatty acids synthesis in 3T3-L1 adipocytes differentiation. Biochim. Biophys. Acta 1859, 1459–1469 (2016).

    Article  CAS  Google Scholar 

  27. Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).

    Article  CAS  Google Scholar 

  28. Hay, N. & Sonenberg, N. Upstream and downstream of mTOR. Genes Dev. 18, 1926–1945 (2004).

    Article  CAS  Google Scholar 

  29. Pause, A. et al. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function. Nature 371, 762–767 (1994).

    Article  CAS  Google Scholar 

  30. Ozcan, U. et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313, 1137–1140 (2006).

    Article  Google Scholar 

  31. Hsieh, A. C. et al. Genetic dissection of the oncogenic mTOR pathway reveals druggable addiction to translational control via 4EBP–eIF4E. Cancer Cell 17, 249–261 (2010).

    Article  CAS  Google Scholar 

  32. Adams, J. M. et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 533–538 (1985).

    Article  CAS  Google Scholar 

  33. Anthony, T. G. et al. Preservation of liver protein synthesis during dietary leucine deprivation occurs at the expense of skeletal muscle mass in mice deleted for eIF2 kinase GCN2. J. Biol. Chem. 279, 36553–36561 (2004).

    Article  CAS  Google Scholar 

  34. Zhang, P. et al. The GCN2 eIF2ɑ kinase is required for adaptation to amino acid deprivation in mice. Mol. Cell Biol. 22, 6681–6688 (2002).

    Article  CAS  Google Scholar 

  35. Masuoka, H. C. & Townes, T. M. Targeted disruption of the activating transcription factor 4 gene results in severe fetal anemia in mice. Blood 99, 736–745 (2002).

    Article  CAS  Google Scholar 

  36. Pytel, D. et al. PERK is a haploinsufficient tumor suppressor: gene dose determines tumor-suppressive versus tumor promoting properties of perk in melanoma. PLoS Genet. 12, e1006518 (2016).

    Article  Google Scholar 

  37. Gao, Y. et al. PERK is required in the adult pancreas and is essential for maintenance of glucose homeostasis. Mol. Cell Biol. 32, 5129–5139 (2012).

    Article  CAS  Google Scholar 

  38. Nguyen, H. G. et al. Development of a stress response therapy targeting aggressive prostate cancer. Sci. Transl. Med. 10, eaar2036 (2018).

    Article  Google Scholar 

  39. Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661–665 (2007).

    Article  CAS  Google Scholar 

  40. Ruggero, D. The role of Myc-induced protein synthesis in cancer. Cancer Res. 69, 8839–8843 (2009).

    Article  CAS  Google Scholar 

  41. Xu, C. & Ng, D. T. Glycosylation-directed quality control of protein folding. Nat. Rev. Mol. Cell Biol. 16, 742–752 (2015).

    Article  CAS  Google Scholar 

  42. Novoa, I., Zeng, H., Harding, H. P. & Ron, D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2ɑ. J. Cell Biol. 153, 1011–1022 (2001).

    Article  CAS  Google Scholar 

  43. Tettweiler, G., Miron, M., Jenkins, M., Sonenberg, N. & Lasko, P. F. Starvation and oxidative stress resistance in Drosophila are mediated through the eIF4E-binding protein, d4E-BP. Genes Dev. 19, 1840–1843 (2005).

    Article  CAS  Google Scholar 

  44. Kremer, C. L. et al. Expression of mTOR signaling pathway markers in prostate cancer progression. Prostate 66, 1203–1212 (2006).

    Article  CAS  Google Scholar 

  45. Karlsson, E. et al. The mTOR effectors 4EBP1 and S6K2 are frequently coexpressed, and associated with a poor prognosis and endocrine resistance in breast cancer: a retrospective study including patients from the randomised Stockholm tamoxifen trials. Breast Cancer Res. 15, R96 (2013).

    Article  Google Scholar 

  46. Cha, Y. L. et al. EIF4EBP1 overexpression is associated with poor survival and disease progression in patients with hepatocellular carcinoma. PLoS ONE 10, e0117493 (2015).

    Article  Google Scholar 

  47. Miao, Y. et al. Increased phosphorylation of 4E-binding protein 1 predicts poor prognosis for patients with colorectal cancer. Mol. Med. Rep. 15, 3099–3104 (2017).

    Article  CAS  Google Scholar 

  48. Kang, M. J. et al. 4E-BP is a target of the GCN2–ATF4 pathway during Drosophila development and aging. J. Cell Biol. 216, 115–129 (2017).

    Article  CAS  Google Scholar 

  49. Yamaguchi, S. et al. ATF4-mediated induction of 4E-BP1 contributes to pancreatic β cell survival under endoplasmic reticulum stress. Cell Metab. 7, 269–276 (2008).

    Article  CAS  Google Scholar 

  50. Pourdehnad, M. et al. Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc. Natl Acad. Sci. USA 110, 11988–11993 (2013).

    Article  CAS  Google Scholar 

  51. Ben-Sahra, I., Hoxhaj, G., Ricoult, S. J. H., Asara, J. M. & Manning, B. D. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 351, 728–733 (2016).

    Article  CAS  Google Scholar 

  52. Cunningham, J. T., Moreno, M. V., Lodi, A., Ronen, S. M. & Ruggero, D. Protein and nucleotide biosynthesis are coupled by a single rate-limiting enzyme, PRPS2, to drive cancer. Cell 157, 1088–1103 (2014).

    Article  CAS  Google Scholar 

  53. Kirchner, S. et al. Alteration of protein function by a silent polymorphism linked to tRNA abundance. PLoS Biol. 15, e2000779 (2017).

    Article  Google Scholar 

  54. Soufi, A., Donahue, G. & Zaret, K. S. Facilitators and impediments of the pluripotency reprogramming factors’ initial engagement with the genome. Cell 151, 994–1004 (2012).

    Article  CAS  Google Scholar 

  55. Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).

    Article  Google Scholar 

  56. Heinz, S. et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).

    Article  CAS  Google Scholar 

  57. Huang da, W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).

    Article  Google Scholar 

  58. Schmitz, R. et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N. Engl. J. Med. 378, 1396–1407 (2018).

    Article  CAS  Google Scholar 

  59. Goldman, M. et al. The UCSC Cancer Genomics Browser: update 2015. Nucleic Acids Res. 43, D812–D817 (2015).

    Article  CAS  Google Scholar 

Download references


We thank D.M. Feldser for critically reading the manuscript. We thank the Koumenis and Maity laboratory members for helpful discussions. This work was supported by National Institutes of Health grants P01CA165997 (D.R., S.Y.F., J.A.D. and C.K.) and 5R01CA198015-04 to R.K.A. F.T. was supported by NIH F31CA183569.

Author information

Authors and Affiliations



F.T. and C.K. conceived the experiments, analysed data and wrote the manuscript. F.T., I.I.V., N.M.L., R.O., C.S., F.C. and A.M.M. performed experiments. C.P. and Z.I. performed tRNA microarray and analysis. C.S.C., J.A.D., S.Y.F. and D.R. provided valuable reagents, important experimental suggestions and helped in manuscript editing. R.K.A. and J.Y. provided important experimental suggestions. A.K. provided bioinformatics support for ChIP–seq data analysis. W.F. and P.W. analysed patient datasets.

Corresponding author

Correspondence to Constantinos Koumenis.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Integrated supplementary information

Supplementary Figure 1 GCN2 is required for optimal activation of ATF4.

a. Representative immunoblot following MYC activation in DLD-1, MycER cells (top) or MEFs, MycER (bottom). b. qPCR showing mRNA expression in GCN2 +/+ and GCN2 -/- : MycER MEFs (left) and DLD-1 MycER cells (right) normalized to 18s RNA. Three independent experiments, error bars represent mean ± SD, two tailed student t -test. c. Heat map of comparative microarray showing tRNA abundance following MYC activation. Data are relative to the control values. tRNA probes are depicted with their cognate codon and the corresponding amino acid; Meti, initiator tRNAMet, four biological replicates, one way-ANOVA, * p=0.018. d. Principal component analysis (PCA) of the changes in the tRNA abundance following MYC activation. All biological replicates (n=4) from tRNA microarrays (2h, 4h and 8h in panel c) were subjected in the analysis. tRNAs charged with different amino acids are color coded as follows: light gray, hydrophobic; dark gray, hydrophilic; blue, positively charged and red, negatively charged amino acids. e. Heat map of comparative microarrays showing tRNA charging following MYC activation in vehicle or 25μM RNA POLIII inhibitor (ML60218) treated cells. f. tRNA microarray of DLD-1: MycER cells pretreated for two hours with vehicle or ML60218 followed by 4hr of MYC induction showing tRNA abundance. Samples were normalized to vehicle treated cells. n=1. Immunoblot are from three independent experiments showing similar results. Unprocessed scans of blots are shown in Supplementary Fig 7.

Supplementary Figure 2 ATF4/MYC ChIP-seq.

a. Previously reported ATF4 targets occupied by ATF4 at 8hr of MYC induction within 5kb from TSS. b. Functions and pathways significantly enriched among genes bound by ATF4 within 5kb from TSS and upregulated at 8 hours of MYC activation, E=enrichment, FDR=false discovery rate, UP=Uniprot, MF=molecular function, BP=biological process. Two independent biological replicates were used for ChIP-seq showing similar result. P-values were calculated by Ingenuity Pathway Analysis using right-tailed Fisher Exact Test with FDR values indicating correction for multiple testing. c. ChIP-qPCR validation of ATF4 target genes (left) and genes bound by both ATF4 and MYC (right). Technical replicates, n=3.

Supplementary Figure 3 Antioxidants, fatty acids or alpha ketoglutarate do not rescue ATF4 deficient cells.

a. Representative immunoblot of ATF4 deficient MEFs treated with indicated antioxidants, Trolox and N-acetyl-cysteine (NAC) or Dimethyl 2-oxoglutarate (αKG) followed by MYC activation. b. Representative immunoblot of ATF4 deficient MEFs treated with indicated fatty acids followed by MYC activation. c. Representative immunoblot of MEFs treated with (αKG) at earlier time points of MYC activation. Immunoblots are representative of two independent experiments showing similar results. Unprocessed scans of blots are shown in Supplementary Fig 7.

Supplementary Figure 4 ATF4 and MYC cooperatively regulate EIF4EBP1.

a. qPCR showing expression of mRNAs in wild type and ATF4 -/-, MycER MEFs normalized to 18s RNA. b. qPCR showing expression of mRNAs in control and ATF4 knockdown DLD-1, MycER cells normalized to 18s RNA. a,b Three independent experiments, error bars represent mean ± SD, two tailed student t-test. c. Representative immunoblot of ATF4 -/-, MycER MEFs pretreated with indicated drugs for 2 hours prior to MYC activation. Rapamycin (Rapa) 200nM. Representative immunoblot from three independent experiments showing similar results. d. Clonogenic survival of ATF4 -/-, MycER MEFs after activation of MYC in the absence or presence of Rapamycin (200nM). Graph from there independent experiments, error bars represent mean ± SD, two tailed student t-test. e.35S incorporation in ATF4 -/-, MycER MEFs following MYC activation. Representative autoradiograph is shown. Graph data from three independent experiments, normalized to β-actin. Error bars represent mean ± SD, two tailed student t-test. f. ATF4-/-, MycER MEFs were pretreated with 5mM 4-Phenylbutyric acid (4PBA) for 2hrs followed by MYC activation. Representative western blot from two independent experiments is shown. g. Annexin V staining of cells transfected with the shown siRNAs, n=2, error bars represent mean ± SEM. Unprocessed scans of blots are shown in Supplementary Fig 7.

Supplementary Figure 5 Loss of GCN2 does not affect MYC driven lymphomagenesis but loss of GCN2 combined with inhibition of PERK promotes survival of MYC driven lymphoma bearing mice.

a. Representative images of genotyping PCR products of mice. PCR was performed more than three times independently. b. Kaplan-Meier analysis for overall survival of Eµ-Myc/+; Gcn2+/+ (n=28), Eµ-Myc/+; Gcn2+/- (n=27) and Eµ-Myc/+; Gcn2-/- mice(n=30). Kaplan-Meier curves were analyzed by two-tailed log-rank test. c. Representative western blot assessing ISR signaling in B cells isolated from tumor bearing mice or WT litter mates. Immunoblot is a representative of 3 independent experiments showing similar results. d. Schematic showing the treatment regimen performed in allograft model of lymphomagenesis. 2 million lymphoma cells were injected via tail vein into mice and LY-4 treatment was started three days after tumor injection. e. Body weight of mice injected with lymphoma cells during LY-4 treatment, (n=8 per each group). f. Pancreas weight of the mice in panel e. n=7 mice per group. Error bars represent mean ± SD, two tailed student t-test. g. Kaplan-Meier analysis for overall survival of mice treated with either vehicle or LY-4 (n=8 per each group). Kaplan-Meier curves were analyzed by two-tailed log-rank test. h. Representative immunoblot of ISR signaling examined in tumors isolated from the indicated groups in panel d at the end of the experiment. i. Quantification of immunoblots for p-eIF2α, including panel c. n = 3 for GCN2 +/+: Veh, n = 6 for GCN2 +/+: LY-4, n = 7 for GCN2 -/-: Veh and GCN2 -/-: LY-4. Error bars represent mean ± SD, two tailed student t-test. Unprocessed scans of blots are shown in Supplementary Fig 8. Unprocessed scans of blots are shown in Supplementary Fig 8.

Supplementary Figure 6 Acute deletion of ATF4 significantly delays MYC driven lymphomagenesis.

a. Schematic showing insertion of LoxP sites in mouse Atf4 locus. Exon 2 and 3, which code for ATF4 protein are deleted after Cre recombinase mediated excision. b. Genotyping PCR products of mice used in in vivo experiments. 1=Eμ-Myc/+, Rosa26CreERT2/+, ATF4+/+ 2= Eμ-Myc/+, Rosa26CreERT2/+, ATF4fl/fl, 3= WT. c. Kaplan-Meier analysis for lymphoma-free survival of mice bearing Eµ-Myc; ATF4+/+ lymphoma treated with either vehicle (veh) or tamoxifen (tam) for 5 days, n=10. Kaplan-Meier curves were analyzed by two-tailed log-rank test. d. mRNA expression of ATF4 from Fig 4d, showing a significant reduction of ATF4 mRNA in B cells treated with tamoxifen, n=3, mice per group. Error bars represent mean ± SD, two tailed student t-test. e. mRNA expression of ATF4 at the endpoint mice treated with vehicle or tamoxifen whose survival is shown in Fig 4b, c. n=3, mice per group. Error bars represent mean ± SD, two tailed student t-test.

Supplementary Figure 7

Unprocessed scans of western blots.

Supplementary information

Supplementary Information

Supplementary Figuress 1–7 and Supplementary Table titles and legends.

Reporting Summary

Supplementary Table 1

List of primers used.

Supplementary Table 2

List of antibodies used.

Supplementary Table 3

Statistics source data.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tameire, F., Verginadis, I.I., Leli, N.M. et al. ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression. Nat Cell Biol 21, 889–899 (2019).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer