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CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels.

Publication ,  Journal Article
Miliani de Marval, P; Lutfeali, S; Jin, JY; Leshin, B; Selim, MA; Zhang, JY
Published in: Cancer Prev Res (Phila)
June 2011

CYLD has been recognized as a tumor suppressor due to its dominant genetic linkage to multiple types of epidermal tumors and a range of other cancers. The molecular mechanisms governing CYLD control of skin cancer are still unclear. Here, we showed that K14-driven epidermal expression of a patient-relevant and catalytically deficient CYLD truncated mutant (CYLD(m)) sensitized mice to skin tumor development in response to 7,12-dimethylbenz[α]anthracene (DMBA)/(12-O-tetradecanoylphorbol-13-acetate) TPA challenge. Tumors developed on transgenic mice were prone to malignant progression and lymph node metastasis and displayed increased activation of c-Jun-NH2-kinase (JNK) and the downstream c-Jun and c-Fos proteins. Most importantly, topical application of a pharmacologic JNK inhibitor significantly reduced tumor development and abolished metastasis in the transgenic mice. Further in line with these animal data, exogenous expression of CYLD(m) in A431, a human squamous cell carcinoma (SCC) cell line, markedly enhanced cell growth, migration, and subcutaneous tumor growth in an AP1-depdendent manner. In contrast, expression of the wild-type CYLD inhibited SCC tumorigenesis and AP1 function. Most importantly, CYLD(m) not only increased JNK activation but also induced an upregulation of K63 ubiquitination on both c-Jun and c-Fos, leading to sustained AP1 activation. Our findings uncovered c-Jun and c-Fos as novel CYLD targets and underscore that CYLD controls epidermal tumorigenesis through blocking the JNK/AP1 signaling pathway at multiple levels.

Duke Scholars

Published In

Cancer Prev Res (Phila)

DOI

EISSN

1940-6215

Publication Date

June 2011

Volume

4

Issue

6

Start / End Page

851 / 859

Location

United States

Related Subject Headings

  • Ubiquitination
  • Tumor Suppressor Proteins
  • Tumor Cells, Cultured
  • Transcription Factor AP-1
  • Tetradecanoylphorbol Acetate
  • Skin Neoplasms
  • Proto-Oncogene Proteins c-jun
  • Proto-Oncogene Proteins c-fos
  • Oncology & Carcinogenesis
  • Mutation
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Miliani de Marval, P., Lutfeali, S., Jin, J. Y., Leshin, B., Selim, M. A., & Zhang, J. Y. (2011). CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels. Cancer Prev Res (Phila), 4(6), 851–859. https://doi.org/10.1158/1940-6207.CAPR-10-0360
Miliani de Marval, Paula, Shazia Lutfeali, Jane Y. Jin, Benjamin Leshin, M Angelica Selim, and Jennifer Y. Zhang. “CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels.Cancer Prev Res (Phila) 4, no. 6 (June 2011): 851–59. https://doi.org/10.1158/1940-6207.CAPR-10-0360.
Miliani de Marval P, Lutfeali S, Jin JY, Leshin B, Selim MA, Zhang JY. CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels. Cancer Prev Res (Phila). 2011 Jun;4(6):851–9.
Miliani de Marval, Paula, et al. “CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels.Cancer Prev Res (Phila), vol. 4, no. 6, June 2011, pp. 851–59. Pubmed, doi:10.1158/1940-6207.CAPR-10-0360.
Miliani de Marval P, Lutfeali S, Jin JY, Leshin B, Selim MA, Zhang JY. CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels. Cancer Prev Res (Phila). 2011 Jun;4(6):851–859.

Published In

Cancer Prev Res (Phila)

DOI

EISSN

1940-6215

Publication Date

June 2011

Volume

4

Issue

6

Start / End Page

851 / 859

Location

United States

Related Subject Headings

  • Ubiquitination
  • Tumor Suppressor Proteins
  • Tumor Cells, Cultured
  • Transcription Factor AP-1
  • Tetradecanoylphorbol Acetate
  • Skin Neoplasms
  • Proto-Oncogene Proteins c-jun
  • Proto-Oncogene Proteins c-fos
  • Oncology & Carcinogenesis
  • Mutation