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.