Opposing roles for calcineurin and ATF3 in squamous skin cancer.

Details

Serval ID
serval:BIB_9D735505178B
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Opposing roles for calcineurin and ATF3 in squamous skin cancer.
Journal
Nature
Author(s)
Wu X., Nguyen B.C., Dziunycz P., Chang S., Brooks Y., Lefort K., Hofbauer G.F., Dotto G.P.
ISSN
1476-4687[electronic], 0028-0836[linking]
Publication state
Published
Issued date
2010
Peer-reviewed
Oui
Volume
465
Number
7296
Pages
368-372
Language
english
Abstract
Calcineurin inhibitors such as cyclosporin A (CsA) are the mainstay of immunosuppressive treatment for organ transplant recipients. Squamous cell carcinoma (SCC) of the skin is a major complication of treatment with these drugs, with a 65 to 100-fold higher risk than in the normal population. By contrast, the incidence of basal cell carcinoma (BCC), the other major keratinocyte-derived tumour of the skin, of melanoma and of internal malignancies increases to a significantly lesser extent. Here we report that genetic and pharmacological suppression of calcineurin/nuclear factor of activated T cells (NFAT) function promotes tumour formation in mouse skin and in xenografts, in immune compromised mice, of H-ras(V12) (also known as Hras1)-expressing primary human keratinocytes or keratinocyte-derived SCC cells. Calcineurin/NFAT inhibition counteracts p53 (also known as TRP53)-dependent cancer cell senescence, thereby increasing tumorigenic potential. ATF3, a member of the 'enlarged' AP-1 family, is selectively induced by calcineurin/NFAT inhibition, both under experimental conditions and in clinically occurring tumours, and increased ATF3 expression accounts for suppression of p53-dependent senescence and enhanced tumorigenic potential. Thus, intact calcineurin/NFAT signalling is critically required for p53 and senescence-associated mechanisms that protect against skin squamous cancer development.
Keywords
Activating Transcription Factor 3/metabolism, Animals, Calcineurin/antagonists & inhibitors, Calcineurin/deficiency, Carcinoma, Squamous Cell/chemically induced, Carcinoma, Squamous Cell/metabolism, Cell Aging, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic/genetics, Cell Transformation, Neoplastic/metabolism, Cells, Cultured, Cyclosporine/pharmacology, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Keratinocytes/metabolism, Keratinocytes/pathology, Mice, Mice, Inbred NOD, Mice, SCID, NFATC Transcription Factors/antagonists & inhibitors, NFATC Transcription Factors/deficiency, Neoplasm Transplantation, Signal Transduction, Skin Neoplasms/chemically induced, Skin Neoplasms/metabolism, Tumor Suppressor Protein p53/metabolism
Pubmed
Web of science
Create date
14/09/2010 15:34
Last modification date
20/08/2019 16:03
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