Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD40 belongs to the tumor necrosis factor (TNF) receptor family. CD40 signaling involves the recruitment of TNF receptor-associated factors (TRAFs) to its cytoplasmic domain. We have identified a novel intracellular CD40-binding protein termed TRAF and TNF receptor-associated protein (TTRAP) that also interacts with TNF-R75 and CD30. The region of the CD40 cytoplasmic domain that is required for TTRAP association overlaps with the TRAF6 recognition motif. Association of TTRAP with CD40 increases profoundly in response to treatment of cells with CD40L. Interestingly, TTRAP also associates with TRAFs, with the highest affinity for TRAF6. In transfected cells, TTRAP inhibits in a dose-dependent manner the transcriptional activation of a nuclear factor-kappaB (NF-kappaB)-dependent reporter mediated by CD40, TNF-R75 or Phorbol 12-myristate 13-acetate (PMA) and to a lesser extent by TRAF2, TRAF6, TNF-alpha, or interleukin-1beta (IL-1beta). TTRAP does not affect stimulation of NF-kappaB induced by overexpression of the NF-kappaB-inducing kinase (NIK), the IkappaB kinase alpha (IKKalpha), or the NF-kappaB subunit P65/RelA, suggesting it acts upstream of the latter proteins. Our results indicate that we have isolated a novel regulatory factor that is involved in signal transduction by distinct members of the TNF receptor family.
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PMID:TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappa B activation. 1076 46

Advances in molecular biology have shed light on the biological basis of Hodgkin's lymphoma (HL). Knowledge of the biological basis has enabled us to understand that most Hodgkin and Reed-Sternberg (H-RS) cells are derived from germinal center B-cells and constitutive nuclear factor kappaB (NF-kappaB) activation is a common molecular feature. Molecular mechanisms responsible for constitutive NF-kappaB activation, Epstein Barr virus latent membrane protein 1, and defective IkappaBalpha and IkappaB kinase activation have been clarified in the past several years. A recent study revealed the biological link between 2 characteristic features of H-RS cells: CD30 overexpression and constitutive NF-kappaB activation. Ligand-independent signaling by overexpressed CD3O was shown to be a common mechanism that induced constitutive NF-kappaB activation in these cells. These results suggest the self-growth-promoting potential of H-RS cells and redefine the biology of HL composed of H-RS cells and lymphocytes.
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PMID:Hodgkin's lymphoma and CD30 signal transduction. 1256 98

In the past several years our understandings for Hodgkin's lymphoma have significantly progressed, and we can now recognize two fundamental bases of Hodgkin's lymphoma: germinal center B cells as a cellular origin of Hodgkin and Reed-Sternberg (H-RS) cells and constitutively strong NF-kappaB activation as a biological base for H-RS cells. We can also define Hodgkin's lymphoma as being composed of H-RS cells with self-growth-promoting potential as malignant cells by constitutively strong NF-kappaB activation and surrounding reactive cells. Identification of molecules involved in constitutive and strong NF-kappaB activation in H-RS cells is important to understand the pathophysiology as well as transformation and developmental process of Hodgkin's lymphoma. Epstein-Barr virus latent membrane protein (LMP)-1, defective IkappaBalpha, IkappaB kinase activation and ligand-independent signaling by overexpressed CD30 have been clarified in the past several years. Involvement of JunB in overexpression of CD30 has been recently reported. Today, over a century and a half after the first report by Thomas Hodgkin, we at last obtained several keys to solving the mystery of Hodgkin's lymphoma on a biological basis.
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PMID:The biological basis of Hodgkin's lymphoma. 1474 44

Overexpression of CD30 and constitutive nuclear factor-kappaB (NF-kappaB) activation are hallmarks of the malignant Hodgkin Reed-Sternberg (H-RS) cells. Previous investigations have demonstrated that both proliferation and survival of H-RS cells require constitutive NF-kappaB activity, which is comprised of the p50 and RelA subunits. We report here enhanced expression of NF-kappaB2/p52 and RelB-containing NF-kappaB DNA-binding activity in Epstein-Barr virus-negative H-RS cells. Kinetic studies revealed that a proteasome inhibitor MG132 induced p100 accumulation with reduced p52 expression in H-RS cells, suggesting proteasome-dependent processing of p100. In addition, treatment with a protein synthesis inhibitor cycloheximide rapidly downregulated inhibitor of NF-kappaB (IkappaB) kinase activity in H-RS cells. We also demonstrate that overexpression of CD30 in rat fibroblasts at levels comparable to those in H-RS cells results in constitutive IkappaB kinase activation, proteasome-dependent p100 processing, and NF-kappaB-dependent cell transformation. Our results thus indicate that CD30 triggers the noncanonical NF-kappaB activation pathway, and suggest that deregulated CD30 signaling contributes to the neoplastic features of H-RS cells.
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PMID:Aberrant NF-kappaB2/p52 expression in Hodgkin/Reed-Sternberg cells and CD30-transformed rat fibroblasts. 1578 19

The ICAM-1/LFA-1 complex mediates cell-cell interaction. ICAM-1 is overexpressed in Hodgkin/Reed-Sternberg (H/RS) cells, and serum levels of its soluble form are higher in Hodgkin's lymphoma (HL) patients than in controls. There are no data, however, regarding the regulation of expression of ICAM-1 in H/RS cells. CD30 was identified in H/RS cells of HL and has attracted much interest as a molecular marker of HL. To analyze ICAM-1 expression in H/RS cells, we examined the expression of ICAM-1, LFA-1, CD30 and CD30L in HL-derived cell lines. All cell lines expressed ICAM-1 and CD30, but not LFA-1 or CD30L. CD30 induced ICAM-1 expression. Analysis of the ICAM-1 promoter showed the importance of NF-kappaB binding site for CD30-induced ICAM-1 gene expression. Coexpression of IkappaB, IKK, NIK and TRAF dominant-negative constructs with CD30 inhibited CD30-induced activation of ICAM-1 promoter, suggesting that CD30 induces ICAM-1 via NF-kappaB signalling. The ICAM-1 promoter was activated by the C-terminal region of CD30, which activated NF-kappaB signalling. A decoy CD30 lacking the cytoplasmic region inhibited ICAM-1 promoter activity in HL cell lines. Thus, in H/RS cells, ligand-independent activation of CD30 signalling activates NF-kappaB and this leads to constitutive ICAM-1 expression, suggesting a link between 2 well known phenotypic characteristics of HL, CD30 and ICAM-1 overexpression.
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PMID:Transactivation of the ICAM-1 gene by CD30 in Hodgkin's lymphoma. 2196 Feb 63

We previously reported that CD30 is induced during lymphocyte transformation and that overexpressed CD30 can transduce ligand-independent signals in Hodgkin lymphoma (HL) cells. However, its biological consequence is not fully addressed. In this study, we examined the effects of targeted repression of overexpressed CD30 on cell signaling and proliferation using small-interfering RNAs (siRNAs) in HL cell lines. Repression of CD30 inhibited cellular proliferation through reduced activation of IkappaB kinase (IKK) and extracellular signal-regulated kinase (ERK) 1/2 in both B- and T-HL cell lines. These HL cell lines bear one or more defects in negative regulators of nuclear factor (NF)-kappaB signaling, including A20, cylindromatosis tumor suppressor protein (CYLD), and IkappaBalpha, and when CD30 is repressed, they show reduced activation of the canonical NF-kappaB pathway. This suggests that CD30 governs NF-kappaB and ERK1/2 signaling pathways, and is involved in the proliferation of HL cells. Defective mutations in negative regulators of NF-kappaB signaling appear to promote CD30-initiated basal NF-kappaB activation. These results indicate that CD30 is involved in the tumorigenic process of HL, and that it may be useful as a therapeutic target for the treatment of HL.
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PMID:Targeted repression of overexpressed CD30 downregulates NF-kappaB and ERK1/2 pathway in Hodgkin lymphoma cell lines. 2271 89