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  • Review Article
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AP-1: a double-edged sword in tumorigenesis

Key Points

  • AP-1 is a dimeric transcription factor that contains members from the JUN, FOS, ATF and MAF protein families.

  • AP-1 activity can be regulated by dimer composition, transcription, post-translational modification and interactions with other proteins.

  • Two of the components of AP-1 — c-JUN and c-FOS — were first identified as viral oncoproteins, so their role in tumorigenesis is well established.

  • However, some JUN and FOS family proteins can suppress tumour formation. The decision as to whether AP-1 is oncogenic or anti-oncogenic depends on the cell type and its differentiation state, tumour stage and the genetic background of the tumour.

  • AP-1 can exert its oncogenic or anti-oncogenic effects by regulating genes involved in cell proliferation, differentiation, apoptosis, angiogenesis and tumour invasion.

  • AP-1 might be a good target for anticancer therapy.

Abstract

The AP-1 transcription factor is a dimeric complex that contains members of the JUN, FOS, ATF and MAF protein families. AP-1 proteins are primarily considered to be oncogenic, but recent studies have challenged this view — some AP-1 proteins, such as JUNB and c-FOS, have been shown to have tumour-suppressor activity. Here, we focus on the JUN and FOS proteins and aim to offer a new perspective on the molecular mechanisms that regulate the oncogenic and anti-oncogenic effects of AP-1 in tumour development.

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Figure 1: The AP-1 transcription factor.
Figure 2: Opposing functions of AP-1 in tumorigenesis.
Figure 3: Transcriptional and post-translational activation of AP-1.
Figure 4: Pro-oncogenic and anti-oncogenic activities of AP-1 in multi-stage tumorigenesis during liver-tumour formation.

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Gian Luca Rampioni Vinciguerra, Marina Capece, … Carlo M. Croce

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Acknowledgements

We are grateful to L. Bakiri, A. Behrens, G. Christofori, A. Fleischmann, M. Sibilia and R. Zenz for helpful comments and critical reading of the manuscript and to H. Tkadletz for help with illustrations. The Research Institute of Molecular Pathology is funded by Boehringer Ingelheim.

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Correspondence to Robert Eferl or Erwin F. Wagner.

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DATABASES

Cancer.gov

bone cancer

brain tumour

liver cancer

lung cancer

osteosarcoma

skin cancer

LocusLink

ATF family

Bcl2

FOS family

FRA1

FRA2

JUN family

MAF family

MAPK

MEF2

RAS

Trp53

FURTHER INFORMATION

International Agency for Research on Cancer

World Health Organization

Glossary

RHABDOMYOSARCOMA

A common soft-tissue sarcoma of childhood, which arises from rhabdomyoblasts (primitive muscle cells). As rhabdomyoblasts are located throughout the body, the tumours can arise at numerous locations, including around the eyes, in the genitourinary tract, at the extremities and in the chest and lungs.

cAMP-RESPONSE ELEMENT

This sequence element is present in the promoters and enhancers of genes that are inducible by cyclic AMP. It is bound by two classes of transcription factors — CREB (CRE-binding) proteins and AP-1 proteins.

KAINATE

This neuroexcitotoxin has been used to model the aetiology of several neurodegenerative disorders. Kainate binds to kainate receptors — a class of ionotropic glutamate receptors — which mediate excitatory synaptic transmission through ligand-induced opening of transmembrane ion channels. Activation of these receptors by kainate can induce neuronal apoptosis, which occurs preferentially in the hippocampal region.

BCL2 FAMILY

BCL2 family members are implicated in programmed cell death, but can be either pro-apoptotic or anti-apoptotic. The anti-apoptotic members prevent the release of apoptogenic molecules from mitochondria, whereas pro-apoptotic family members function as sentinels for cellular damage — cytotoxic signals induce their translocation to organelles where they bind to their pro-survival relatives, promote organelle damage and trigger apoptosis.

MYOCYTE-ENHANCER FACTOR 2

The four MEF2 transcription factors (MEF2A to MEF2D) regulate calcium-dependent gene expression in muscle cells and have a pivotal role in the differentiation of cardiac and skeletal muscle. The expression of muscle-specific genes is often accomplished through MEF2-responsive elements (MEF2 sites) and recognition elements for other muscle-specific transcription factors, such as MyoD and myogenin.

K5–SOS TRANSGENE

This transgene directs the ectopic expression of the constitutively active human SOS protein in keratinocytes as it is under the control of the keratin-5 promoter. SOS functions upstream of RAS in the receptor tyrosine kinase MAPK pathway and induces skin papillomas in K5–SOS transgenic mice.

TRANSREPRESSION

Mutual negative interference between transcription factors. Examples are the interactions between the glucocorticoid receptor (GR) and other transcription factors, such as CREB, AP-1, NF-κB and OCT1. The GR attenuates the activity of these transcription factors by direct protein–protein interaction, without the need for DNA-binding. AP-1 is also transrepressed by retinoic-acid receptors, the oestrogen receptor, the thyroid receptor and the fusion receptor PML–RAR.

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Eferl, R., Wagner, E. AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 3, 859–868 (2003). https://doi.org/10.1038/nrc1209

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