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

Publication ,  Journal Article
Ke, H; Augustine, CK; Gandham, VD; Jin, JY; Tyler, DS; Akiyama, SK; Hall, RP; Zhang, JY
Published in: J Invest Dermatol
January 2013

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.

Duke Scholars

Published In

J Invest Dermatol

DOI

EISSN

1523-1747

Publication Date

January 2013

Volume

133

Issue

1

Start / End Page

221 / 229

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Suppressor Protein p53
  • Tumor Necrosis Factor-alpha
  • Transcription Factors
  • Transcription Factor AP-1
  • Skin Neoplasms
  • Proto-Oncogene Proteins c-jun
  • Proto-Oncogene Proteins
  • Mutation
  • Melanoma
 

Citation

APA
Chicago
ICMJE
MLA
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Ke, H., Augustine, C. K., Gandham, V. D., Jin, J. Y., Tyler, D. S., Akiyama, S. K., … Zhang, J. 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), 221–229. https://doi.org/10.1038/jid.2012.253
Ke, Hengning, Christina K. Augustine, Vineela D. Gandham, Jane Y. Jin, Douglas S. Tyler, Steven K. Akiyama, Russell P. Hall, and Jennifer Y. Zhang. “CYLD inhibits melanoma growth and progression through suppression of the JNK/AP-1 and β1-integrin signaling pathways.J Invest Dermatol 133, no. 1 (January 2013): 221–29. https://doi.org/10.1038/jid.2012.253.
Ke H, Augustine CK, Gandham VD, Jin JY, Tyler DS, Akiyama SK, et al. CYLD inhibits melanoma growth and progression through suppression of the JNK/AP-1 and β1-integrin signaling pathways. J Invest Dermatol. 2013 Jan;133(1):221–9.
Ke, Hengning, et al. “CYLD inhibits melanoma growth and progression through suppression of the JNK/AP-1 and β1-integrin signaling pathways.J Invest Dermatol, vol. 133, no. 1, Jan. 2013, pp. 221–29. Pubmed, doi:10.1038/jid.2012.253.
Ke H, Augustine CK, Gandham VD, Jin JY, Tyler DS, Akiyama SK, Hall RP, Zhang JY. CYLD inhibits melanoma growth and progression through suppression of the JNK/AP-1 and β1-integrin signaling pathways. J Invest Dermatol. 2013 Jan;133(1):221–229.
Journal cover image

Published In

J Invest Dermatol

DOI

EISSN

1523-1747

Publication Date

January 2013

Volume

133

Issue

1

Start / End Page

221 / 229

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Tumor Suppressor Protein p53
  • Tumor Necrosis Factor-alpha
  • Transcription Factors
  • Transcription Factor AP-1
  • Skin Neoplasms
  • Proto-Oncogene Proteins c-jun
  • Proto-Oncogene Proteins
  • Mutation
  • Melanoma