A novel NF-kappa B-inducing kinase-MAPK signaling pathway up-regulates NF-kappa B activity in melanoma cells.

Abstract

Constitutive activation of NF-kappa B is an emerging hallmark of various types of tumors including breast, colon, pancreatic, ovarian, and melanoma. In melanoma cells, the basal expression of the CXC chemokine, CXCL1, is constitutively up-regulated. This up-regulation can be attributed in part to constitutive activation of NF-kappa B. Previous studies have shown an elevated basal I kappa B kinase (IKK) activity in Hs294T melanoma cells, which leads to an increased rate of I kappa B phosphorylation and degradation. This increase in I kappa B-alpha phosphorylation and degradation leads to an approximately 19-fold higher nuclear localization of NF-kappa B. However, the upstream IKK kinase activity is up-regulated by only about 2-fold and cannot account for the observed increase in NF-kappa B activity. We now demonstrate that NF-kappa B-inducing kinase (NIK) is highly expressed in melanoma cells, and IKK-associated NIK activity is enhanced in these cells compared with the normal cells. Kinase-dead NIK blocked constitutive NF-kappa B or CXCL1 promoter activity in Hs294T melanoma cells, but not in control normal human epidermal melanocytes. Transient overexpression of wild type NIK results in increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), which is inhibited in a concentration-dependent manner by PD98059, an inhibitor of p42/44 MAPK. Moreover, the NF-kappa B promoter activity decreased with overexpression of dominant negative ERK expression constructs, and EMSA analyses further support the hypothesis that ERK acts upstream of NF-kappa B and regulates the NF-kappa B DNA binding activity. Taken together, our data implicate involvement of I kappa B kinase and MAPK signaling cascades in NIK-induced constitutive activation of NF-kappa B.

• Authors: Punita Dhawan, Ann Richmond
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 277 Issue 10 Pg. 7920-8 (Mar 08 2002) ISSN: 0021-9258 [Print] United States
• PMID: 11773061 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Enzyme Inhibitors
• Flavonoids
• NF-kappa B
• DNA
• Mitogen-Activated Protein Kinases
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Active Transport, Cell Nucleus
• Cell Line
• DNA (metabolism)
• Dose-Response Relationship, Drug
• Enzyme Activation
• Enzyme Inhibitors (pharmacology)
• Flavonoids (pharmacology)
• Humans
• MAP Kinase Signaling System
• Melanoma (enzymology, metabolism)
• Mitogen-Activated Protein Kinases (metabolism)
• Models, Biological
• Mutation
• NF-kappa B (metabolism)
• Plasmids (metabolism)
• Promoter Regions, Genetic
• Protein Binding
• Signal Transduction
• Time Factors
• Transfection
• Tumor Cells, Cultured
• Up-Regulation