The lymphotoxin-beta receptor is an upstream activator of NF-kappaB-mediated transcription in melanoma cells.

Abstract

The pleiotropic transcription factor nuclear factor-kappaB (NF-kappaB (p50/p65)) regulates the transcription of genes involved in the modulation of cell proliferation, apoptosis, and oncogenesis. Furthermore, a host of solid and hematopoietic tumor types exhibit constitutive activation of NF-kappaB (Basseres, D. S., and Baldwin, A. S. (2006) 25, 6817-6830). However, the mechanism for this constitutive activation of NF-kappaB has not been elucidated in the tumors. We have previously shown that NF-kappaB-inducing kinase (NIK) protein and its association with Inhibitor of kappaB kinase alphabeta are elevated in melanoma cells compared with their normal counterpart, leading to constitutive activation of NF-kappaB. Moreover, expression of dominant negative NIK blocked this base-line NF-kappaB activity in melanoma cells. Of the three receptors that require NIK for activation of NF-kappaB, only the lymphotoxin-beta receptor (LTbeta-R) is expressed in melanoma. We show in this manuscript that for melanoma there is a strong relationship between expression of the LTbeta-R and constitutive NF-kappaB transcriptional activity. Moreover, we show that activation of the LTbeta-R can drive NF-kappaB activity to regulate gene expression that leads to enhanced cell growth. The inhibition by LTbeta-R shRNA resulted in decreased NF-kappaB promoter activity, decreased growth, and decreased invasiveness as compared with control. These results indicate that the LTbeta-R constitutively induces NF-kappaB activation, and this event may be associated with autonomous growth of melanoma cells.

• Authors: Punita Dhawan, Yingjun Su, Yee Mon Thu, Yingchun Yu, Paige Baugher, Darrel L Ellis, Tammy Sobolik-Delmaire, Mark Kelley, Timothy C Cheung, Carl F Ware, Ann Richmond
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 283 Issue 22 Pg. 15399-408 (May 30 2008) ISSN: 0021-9258 [Print] United States
• PMID: 18347013 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Lymphotoxin beta Receptor
• NF-kappa B
• Neoplasm Proteins
• Protein Serine-Threonine Kinases
• I-kappa B Kinase
• NF-kappa B kinase

Topics

• Apoptosis
• Cell Line, Tumor
• Cell Proliferation
• Gene Expression Regulation, Neoplastic
• Humans
• I-kappa B Kinase (metabolism)
• Lymphotoxin beta Receptor (metabolism)
• Melanoma (metabolism, pathology)
• NF-kappa B (metabolism)
• Neoplasm Invasiveness
• Neoplasm Proteins (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Transcription, Genetic