Ras, protein kinase C zeta, and I kappa B kinases 1 and 2 are downstream effectors of CD44 during the activation of NF-kappa B by hyaluronic acid fragments in T-24 carcinoma cells
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2000-02-05Keywords
AnimalsAntigens, CD44
DNA-Binding Proteins
Dose-Response Relationship, Immunologic
Gene Expression Regulation, Neoplastic
Genes, Reporter
Humans
Hyaluronic Acid
I-kappa B Kinase
*I-kappa B Proteins
Isoenzymes
Mice
Molecular Weight
NF-kappa B
Phosphorylation
Protein Kinase C
Protein-Serine-Threonine Kinases
Tumor Cells, Cultured
Urinary Bladder Neoplasms
ras Proteins
Immunology and Infectious Disease
Metadata
Show full item recordAbstract
We have investigated the ability of hyaluronic acid (HA) fragments to activate the transcription factor NF-kappa B. HA fragments activated NF-kappa B in the cell lines T-24, HeLa, MCF7, and J774. Further studies in T-24 cells demonstrated that HA fragments also induced I kappa B alpha phosphorylation and degradation, kappa B-linked reporter gene expression, and ICAM-1 promoter activity in an NF-kappa B-dependent manner. The effect of HA was size dependent as neither disaccharide nor native HA were active. CD44, the principal cellular receptor for HA, was critical for the response because the anti-CD44 Ab IM7.8.1 blocked the effect on NF-kappa B. HA fragments activated the I kappa B kinase complex, and the effect on a kappa B-linked reporter gene was blocked in T-24 cells expressing dominant negative I kappa B kinases 1 or 2. Activation of protein kinase C (PKC) was required because calphostin C inhibited NF-kappa B activation and I kappa B alpha phosphorylation. In particular, PKC zeta was required because transfection of cells with dominant negative PKC zeta blocked the effect of HA fragments on kappa B-linked gene expression and HA fragments increased PKC zeta activity. Furthermore, damnacanthal and manumycin A, two mechanistically distinct inhibitors of Ras, blocked NF-kappa B activation. Transfection of T-24 cells with dominant negative Ras (RasN17) blocked HA fragment-induced kappa B-linked reporter gene expression, and HA fragments activated Ras activity within 5 min. Taken together, these studies establish a novel signal transduction cascade emanating from CD44 to Ras, PKC zeta, and I kappa B kinase 1 and 2.Source
J Immunol. 2000 Feb 15;164(4):2053-63.Permanent Link to this Item
http://hdl.handle.net/20.500.14038/34873PubMed ID
10657658Related Resources
Link to Article in PubMedCollections
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