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CYLD inhibits melanoma growth and progression through suppression of the JNK/AP-1 and β1-integrin signaling pathways.

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Date
2013-01
Authors
Ke, Hengning
Augustine, Christina K
Gandham, Vineela D
Jin, Jane Y
Tyler, Douglas S
Akiyama, Steven K
Hall, Russell P
Zhang, Jennifer Y
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Abstract
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.
Type
Journal article
Subject
Antigens, CD
Antigens, CD29
Cadherins
Cell Adhesion
Cell Line, Tumor
Cell Proliferation
Collagen Type IV
Cyclin D1
Disease Progression
Humans
MAP Kinase Kinase 7
MAP Kinase Signaling System
Melanoma
Mutation
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-jun
Skin Neoplasms
Transcription Factor AP-1
Transcription Factors
Tumor Necrosis Factor-alpha
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
Permalink
https://hdl.handle.net/10161/15169
Published Version (Please cite this version)
10.1038/jid.2012.253
Publication Info
Ke, Hengning; Augustine, Christina K; Gandham, Vineela D; Jin, Jane Y; Tyler, Douglas S; Akiyama, Steven K; ... Zhang, Jennifer Y (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 https://hdl.handle.net/10161/15169.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Hall

Russell P. Hall III

J. Lamar Callaway Distinguished Professor of Dermatology, in the School of Medicine
Our laboratory is investigating the pathogenesis of autoimmune blistering skin diseases. Areas of special expertise include immune mediated skin diseases, especially immune mediated primary blistering disorders. These include pathogenesis, diagnosis, and management. Specifically our laboratory is investigating the role of the mucosal immune response in the pathogenesis of dermatitis herpetiformis (DH) and the role the associated gluten sensitive enteropathy (GSE) plays in the development o
Zhang

Jennifer Yunyan Zhang

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
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