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

Dhawan P, Su Y, Thu YM, Yu Y, Baugher P, Ellis DL, Sobolik-Delmaire T, Kelley M, Cheung TC, Ware CF, Richmond A
J Biol Chem. 2008 283 (22): 15399-408

PMID: 18347013 · PMCID: PMC2397477 · DOI:10.1074/jbc.M708272200

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.

MeSH Terms (13)

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

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