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AP1 factor inactivation in the suprabasal epidermis causes increased epidermal hyperproliferation and hyperkeratosis but reduced carcinogen-dependent tumor formation

Oncogene volume 29, pages 5873–5882 (2010)Cite this article

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Abstract

Activator protein one (AP1) (jun/fos) factors comprise a family of transcriptional regulators (c-jun, junB, junD, c-fos, FosB, Fra-1 and Fra-2) that are key controllers of epidermal keratinocyte survival and differentiation, and are important drivers of cancer development. Understanding the role of these factors in epidermis is complicated by the fact that each member is expressed in defined cell layers during epidermal differentiation, and because AP1 factors regulate competing processes (that is, proliferation, apoptosis and differentiation). We have proposed that AP1 factors function differently in basal versus suprabasal epidermis. To test this, we inactivated suprabasal AP1 factor function in mouse epidermis by targeted expression of dominant-negative c-jun (TAM67), which inactivates function of all AP1 factors. This produces increased basal keratinocyte proliferation, delayed differentiation and extensive hyperkeratosis. These findings contrast with previous studies showing that basal layer AP1 factor inactivation does not perturb resting epidermis. It is interesting that in spite of extensive keratinocyte hyperproliferation, susceptibility to carcinogen-dependent tumor induction is markedly attenuated. These novel observations strongly suggest that AP1 factors have distinct roles in the basal versus suprabasal epidermis, confirm that AP1 factor function is required for normal terminal differentiation, and suggest that AP1 factors have a different role in normal epidermis versus cancer progression.

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Abbreviations

TRE or TetO:

tetracycline response element

TAM67:

dominant-negative c-jun

K1:

keratin 1

K14:

keratin 14

K5:

keratin 5

rTA:

tetracycline-responsive activator protein

TPA:

12-O-tetradecanoylphorbol-13-acetate

DMBA:

7, 12-dimethylbenzanthracene

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Acknowledgements

This work was supported by NIH RO1 AR046494 (R Eckert).

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Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA

    E A Rorke

  2. Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA

    G Adhikary, R Jans & R L Eckert

  3. Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, OH, USA

    J F Crish

  4. Department of Dermatology, University of Maryland School of Medicine, Baltimore, MD, USA

    R L Eckert

  5. Department of Obstetrics and Genecology and Reproductive Sciences, University of Maryland School of Medicine, Baltimore, MD, USA

    R L Eckert

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  1. E A Rorke
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Rorke, E., Adhikary, G., Jans, R. et al. AP1 factor inactivation in the suprabasal epidermis causes increased epidermal hyperproliferation and hyperkeratosis but reduced carcinogen-dependent tumor formation. Oncogene 29, 5873–5882 (2010). https://doi.org/10.1038/onc.2010.315

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