西亚试剂优势供应上万种化学试剂产品，欢迎各位新老客户咨询、选购！
中国
联系我们
联系方式：400-990-3999 / 邮箱：sales@xiyashiji.com
西亚试剂 —— 品质可靠，值得信赖
Opposing roles for calcineurin and ATF3 in squamous skin cancer
Xunwei Wu1, Bach-Cuc Nguyen1, Piotr Dziunycz2, Sungeun Chang1,4, Yang Brooks1, Karine Lefort3, Günther F. L. Hofbauer2 & G. Paolo Dotto1,3
1Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA
2Department of Dermatology, University Hospital Zurich, Zürich CH-8091
3Department of Biochemistry, University of Lausanne, Epalinges CH-1066, Switzerland
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 population1. 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 extent1. 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-rasV12 (also known as Hras1)-expressing primary human keratinocytes or keratinocyte-derived SCC cells. Calcineurin/NFAT inhibition counteracts (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.
