CYLD inhibits melanoma growth and progression through suppression of the JNK/AP-1 and β1-integrin signaling pathways.
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The molecular mechanisms mediating cylindromatosis (CYLD) tumor suppressor function appear to be manifold. Here, we demonstrate that, in contrast to the increased levels of phosphorylated c-Jun NH(2)-terminal kinase (pJNK), CYLD was decreased in a majority of the melanoma cell lines and tissues examined. Exogenous expression of CYLD but not its catalytically deficient mutant markedly inhibited melanoma cell proliferation and migration in vitro and subcutaneous tumor growth in vivo. In addition, the melanoma cells expressing exogenous CYLD were unable to form pulmonary tumor nodules following tail-vein injection. At the molecular level, CYLD decreased β1-integrin and inhibited pJNK induction by tumor necrosis factor-α or cell attachment to collagen IV. Moreover, CYLD induced an array of other molecular changes associated with modulation of the "malignant" phenotype, including a decreased expression of cyclin D1, N-cadherin, and nuclear Bcl3, and an increased expression of p53 and E-cadherin. Most interestingly, coexpression of the constitutively active MKK7 or c-Jun mutants with CYLD prevented the above molecular changes, and fully restored melanoma growth and metastatic potential in vivo. Our findings demonstrate that the JNK/activator protein 1 signaling pathway underlies the melanoma growth and metastasis that are associated with CYLD loss of function. Thus, restoration of CYLD and inhibition of JNK and β1-integrin function represent potential therapeutic strategies for treatment of malignant melanoma.
Cell Line, Tumor
Collagen Type IV
MAP Kinase Kinase 7
MAP Kinase Signaling System
Proto-Oncogene Proteins c-jun
Transcription Factor AP-1
Tumor Necrosis Factor-alpha
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Published Version (Please cite this version)10.1038/jid.2012.253
Publication InfoAkiyama, SK; Augustine, CK; Gandham, VD; Hall, RP; Jin, JY; Ke, H; ... Zhang, Jennifer (2013). CYLD inhibits melanoma growth and progression through suppression of the JNK/AP-1 and β1-integrin signaling pathways. J Invest Dermatol, 133(1). pp. 221-229. 10.1038/jid.2012.253. Retrieved from http://hdl.handle.net/10161/15169.
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Associate Professor in Dermatology
Epidermis of the skin constitutes the largest organ and the outer most barrier of the body. It is one of the few organs that undergo lifelong self-renewal through a tight balance of cell growth, differentiation, and programmed cell death. Deregulation of this balance is manifested in many diseases, including various immune diseases and cancer. Our lab is focused on 3 interrelated topics: 1. Gene regulation of epithelial cell proliferation and differenti