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Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1): a master regulator of mRNA translation involved in tumorigenesis

Oncogene volume 35, pages 4675–4688 (2016)Cite this article

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Abstract

Protein synthesis activity is abnormally enhanced in cancer cells to support their uncontrolled growth. However, this process needs to be tightly restricted under metabolic stress-a condition often found within the tumor microenvironment-to preserve cell viability. mTORC1 is critical to link protein synthesis activity to nutrient and oxygen levels, in part by controlling the 4E-BP1-eIF4E axis. Whereas mTORC1 and eIF4E are known pro-tumorigenic factors, whose expression or activity is increased in numerous cancers, the role of 4E-BP1 in cancer is not yet definitive. On the one hand, 4E-BP1 has tumor suppressor activity by inhibiting eIF4E and, thus, blocking mRNA translation and proliferation. This is corroborated by elevated levels of phosphorylated and hence inactive 4E-BP1, which are detected in various cancers. On the other hand, 4E-BP1 has pro-tumorigenic functions as it promotes tumor adaptation to metabolic and genotoxic stress by selectively enhancing or preventing the translation of specific transcripts. Here we describe the molecular and cellular functions of 4E-BP1 and highlight the distinct roles of 4E-BP1 in cancer depending on the microenvironmental context of the tumor.

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Abbreviations

(p-)4E-BP1:

(Phosphorylated) Eukaryotic initiation factor 4E-binding protein 1

AMP:

Adenosine monophosphate

AMPK:

AMP-activated protein kinase

asTORi:

Active-site TOR inhibitor

ATM:

Ataxia telangiectasia mutated

ADP:

Adenosine diphosphate

AMP:

Adenosine monophosphate

ATP:

Adenosine triphosphate

BNIP:

BCL2/adenovirus E1B 19-kDa protein-interacting protein

BRAF:

B-Raf proto-oncogene, serine/threonine kinase

CDK1,2:

Cyclin dependent kinases 1, 2

CREF:

Cloned rat embryo fibroblast

DNA:

Desoxyribonucleic acid

EGFR:

epidermal growth factor receptor

eIF3:

Eukaryotic initiation factor 3

eIF4E,A,G,F:

Eukaryotic initiation factor 4 E, A, G, F

EMT:

Epithelial-mesenchymal transition

ERK:

Extracellular signal-regulated kinase

FGF2:

Fibroblast growth factor 2

Gas2:

Growth arrest-specific protein 2

GSK3:

Glycogen synthase kinase 3

GTP:

Guanosine triphosphate

HIF-1α:

Hypoxia-inducable factor 1-α

IKKβ:

Inhibitor of kappa light polypeptide gene enhancer in B-cells kinase beta

IRES:

Internal ribosome entry sites

LKB1:

Liver kinase B 1

MAPK:

Mitogen-activated protein kinase

MEF:

Mouse embryonic fibroblast

MMP9:

Matrix metalloproteinase 9

(m)RNA:

(Messenger) ribonucleic acid

mTOR:

Mammalian target of rapamycin

mTORC1, 2:

mTOR complex 1, 2

ODC:

Ornithine decarboxylase

PABP:

Poly-A-binding protein

PA:

Phosphatidic acid

PDGFRB:

platelet-derived growth factor receptor, beta polypeptide

PI3K:

Phosphatidyl-inositide-3 kinase

PML:

Promyelocytic leukemia

PTEN:

Phosphatase and tensin homolog

Raptor:

Regulatory-associated protein of mTOR

REDD1:

Regulated in development and DNA damage response 1

Rheb:

Ras homolog enriched in brain

RSK1:

Ribosomal S6 kinase 1

S6K1,2:

Ribosomal protein S6 kinase 1, 2

shRNA:

Short-hairpin RNA

TNFα:

Tumor necrosis factor α

TNM:

tumor-nodes-metastasis classification

TOP:

Terminal oligopyrimidine tract

TSC:

Tuberous sclerosis complex

UTR:

Untranslated region

v-ATPase:

Vacuolar H+- ATPase

VEGF:

Vascular endothelial growth factor.

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Acknowledgements

JM is supported by a scholarship in frame of the ‘Deutschlandstipendium’ program of the Bundesministerium für Bildung und Forschung (BMBF) and the LMU Munich. MD is supported by a grant of the ‘Deutsche Stiftung für Junge Erwachsene mit Krebs’. TGPG is supported by a grant from the ‘Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultät der LMU München (WiFoMed)’, the Daimler and Benz Foundation in cooperation with the Reinhard Frank Foundation, by LMU Munich’s Institutional Strategy LMUexcellent within the framework of the German Excellence Initiative, the ‘Mehr LEBEN für krebskranke Kinder – Bettina-Bräu-Stiftung’, the Fritz-Thyssen Foundation (FTF-40.15.0.030MN), the Deutsche Forschungsgemeinschaft (DFG GR3728/2-1) and by the German Cancer Aid (DKH-111886).

Author contributions

JM, BR, TK, GL and TGPG conceived and wrote this paper. All authors contributed in literature survey as well as in drafting of the figures and the tables.

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Authors and Affiliations

  1. Laboratory for Pediatric Sarcoma Biology, Institute of Pathology of the LMU Munich, Munich, Germany

    J Musa, M F Orth, M Dallmayer, M Baldauf & T G P Grünewald

  2. Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel

    C Pardo, B Rotblat & G Leprivier

  3. Institute of Pathology of the LMU Munich, Munich, Germany

    T Kirchner

  4. German Cancer Consortium (DKTK), Heidelberg, Germany

    T Kirchner

  5. German Cancer Research Center (DKFZ), Heidelberg, Germany

    T Kirchner

  6. The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel

    G Leprivier

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  1. J Musa
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Musa, J., Orth, M., Dallmayer, M. et al. Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1): a master regulator of mRNA translation involved in tumorigenesis. Oncogene 35, 4675–4688 (2016). https://doi.org/10.1038/onc.2015.515

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