A new MAFia in cancer

Key Points

  • Maf proteins are bZIP transcription factors of the AP1 superfamily, like JUN and FOS.

  • During development, Maf proteins are involved early during tissue specification and later in terminal differentiation.

  • Large Maf proteins, MAFA, MAFB and MAF, are bona fide oncogenes, as demonstrated in tissue culture and animal models and in human cancer.

  • In humans, the large Maf are overexpressed in 50% of multiple myelomas and 60% of angioimmunoblastic T-cell lymphomas. In particular, MAF, MAFB and MAFA genes are translocated to the immunoglobulin heavy chain locus in 8–10% of multiple myelomas.

  • The transforming activity of large Maf proteins is context-dependent and they can occasionally display tumour suppressor-like activity in specific cellular settings.

  • Their transforming activity relies on overexpression, and is regulated by post-translational modifications, notably phosphorylation.

  • In several biological settings, large Maf induce deregulation of cell cycle, cell migration and cell–cell interactions through induction of expression of cyclin D2, ARK5 and integrin β7, respectively.

  • The oncogenic activity of Maf may result, in part, from the acquisition of novel functions.

  • A striking characteristic of Maf proteins in oncogenesis is their ability to enhance the interaction between tumour cells and stromal cells.

Abstract

Like JUN and FOS, the Maf transcription factors belong to the AP1 family. Besides their established role in human cancer — overexpression of the large Maf genes promotes the development of multiple myeloma — they can display tumour suppressor-like activity in specific cellular contexts, which is compatible with their physiological role in terminal differentiation. However, their oncogenic activity relies mostly on the acquisition of new biological functions relevant to cell transformation, the most striking characteristic of Maf oncoproteins being their ability to enhance pathological interactions between tumour cells and the stroma.

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Figure 1: Maf proteins, members of the AP1 superfamily.
Figure 2: Post-translational modifications regulate large Maf biochemical activities.
Figure 3: A model for Maf functions in cancer.

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Acknowledgements

The authors would like to thank the members of the laboratory for helpful discussions and C. Tran Quang, M. Mhlanga and G. Kirchweger for critical reading of the manuscript. A.E.'s laboratory is funded by grants from the INCa (French National Institute of Cancer), the Association pour la Recherche sur le Cancer and the Ligue Nationale contre le Cancer.

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Correspondence to Celio Pouponnot.

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DATABASES

European Bioinformatics Institute

bZIP

National Cancer Institute

chronic myelogenous leukaemia

multiple myeloma

National Cancer Institute Drug Dictionary

bortezomib

Pfam

bZIP

OMIM

retinitis pigmentosa

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Multiple myeloma

National Laboratory for Computational Science and Engineering

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Immediate early genes

Genes that show rapid and transient expression in the absence of de novo protein synthesis following stimulation by extracellular signals such as growth factors.

Pulverulent cataract

Cataract is a cause of blindness resulting from an opacity that develops in the crystalline lens of the eye or in its envelope. Pulverulent cataracts are characterized by powdery (pulverised) opacities that may be found in any part of the lens.

Clumped pigmentary retinal degeneration

An inherited retinal disorder also known as the enhanced S-cone syndrome or Goldmann–Favre syndrome, which involves retinal degeneration accompanied by clusters of large, clumped pigment deposits in the peripheral fundus at the level of the retinal pigment epithelium.

Retinitis pigmentosa

Refers to a group of inherited diseases causing retinal degeneration characterized by abnormalities of the photoreceptors (rods and cones) or of the retinal pigment epithelium, leading to progressive vision loss.

Angioimmunoblastic T-cell lymphoma

An aggressive peripheral T-cell lymphoma previously known as angioimmunoblastic lymphadenopathy with dysproteinaemia. It represents disease ranging from a hyperplastic but still benign immune reaction to frank malignant lymphoma.

Extracellular matrix

(ECM). Complex three-dimensional network of macromolecular protein fibres as well as non-fibrous proteoglycans that is present between clusters of cells in the stroma of all tissues. The ECM provides architectural structure and strength and contextual information for cellular communication, adhesion and migration.

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Eychène, A., Rocques, N. & Pouponnot, C. A new MAFia in cancer. Nat Rev Cancer 8, 683–693 (2008). https://doi.org/10.1038/nrc2460

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