title: 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.affiliation: Department of Veterans Affairs, Nashville, TN 37212, USA.
authors.forename: Punita
authors.initials: P
authors.lastname: Dhawan
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Su
authors.forename: Yee Mon
authors.initials: YM
authors.lastname: Thu
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Yu
authors.forename: Paige
authors.initials: P
authors.lastname: Baugher
authors.forename: Darrel L
authors.initials: DL
authors.lastname: Ellis
authors.forename: Tammy
authors.initials: T
authors.lastname: Sobolik-Delmaire
authors.forename: Mark
authors.initials: M
authors.lastname: Kelley
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Cheung
authors.forename: Carl F
authors.initials: CF
authors.lastname: Ware
authors.forename: Ann
authors.initials: A
authors.lastname: Richmond
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D053259:Lymphotoxin beta Receptor / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D051550:I-kappa B Kinase; D053259:Lymphotoxin beta Receptor; D016328:NF-kappa B; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase