Opposing roles for calcineurin and ATF3 in squamous skin cancer.

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Date

20 mai 2010

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Périmètre
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Serveur académique Lausannois

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Ce document est lié à :
info:eu-repo/semantics/altIdentifier/doi/10.1038/nature08996

Ce document est lié à :
info:eu-repo/semantics/altIdentifier/pmid/20485437

Ce document est lié à :
info:eu-repo/semantics/altIdentifier/eissn/1476-4687

Ce document est lié à :
info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_9D735505178B2

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Serveur Académique Lausannois

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Université de Lausanne et CHUV

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info:eu-repo/semantics/openAccess , Copying allowed only for non-profit organizations , https://serval.unil.ch/disclaimer

Mots-clés 0

Activating Transcription Factor 3/metabolism; Animals; Calcineurin/deficiency; Calcineurin/genetics; Calcineurin/metabolism; Calcineurin Inhibitors; Carcinoma, Squamous Cell/chemically induced; Carcinoma, Squamous Cell/metabolism; Carcinoma, Squamous Cell/pathology; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic/genetics; Cell Transformation, Neoplastic/metabolism; Cells, Cultured; Cellular Senescence; 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; NFATC Transcription Factors/genetics; NFATC Transcription Factors/metabolism; Neoplasm Transplantation; Signal Transduction; Skin Neoplasms/chemically induced; Skin Neoplasms/metabolism; Skin Neoplasms/pathology; Tumor Suppressor Protein p53/metabolism

Sujets proches En

Integument (Skin) Cutis

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X. Wu et al., « Opposing roles for calcineurin and ATF3 in squamous skin cancer. », Serveur académique Lausannois, ID : 10.1038/nature08996

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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.

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