Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor alpha (TNF alpha) enhances proliferation of chemically-induced mammary tumors and of T47D human cell line through not fully understood pathways. Here, we explored the intracellular signaling pathways triggered by TNF alpha, the participation of TNF alpha receptor (TNFR) 1 and TNFR2 and the molecular mechanism leading to breast cancer growth. We demonstrate that TNFalpha induced proliferation of C4HD murine mammary tumor cells and of T47D cells through the activation of p42/p44 MAPK, JNK, PI3-K/Akt pathways and nuclear factor-kappa B (NF-kappa B) transcriptional activation. A TNF alpha-specific mutein selectively binding to TNFR1 induced p42/p44 MAPK, JNK, Akt activation, NF-kappa B transcriptional activation and cell proliferation, just like wild-type TNF alpha, while a mutein selective for TNFR2 induced only p42/p44 MAPK activation. Interestingly, blockage of TNFR1 or TNFR2 with specific antibodies was enough to impair TNF alpha signaling and biological effect. Moreover, in vivo TNF alpha administration supported C4HD tumor growth. We also demonstrated, for the first time, that injection of a selective inhibitor of NF-kappa B activity, Bay 11-7082, resulted in regression of TNF alpha-promoted tumor. Bay 11-7082 blocked TNF alpha capacity to induce cell proliferation and up-regulation of cyclin D1 and of Bcl-xLin vivo and in vitro. Our results reveal evidence for TNF alpha as a breast tumor promoter, and provide novel data for a future therapeutic approach using TNF alpha antagonists and NF-kappa B pharmacological inhibitors in established breast cancer treatment.
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PMID:TNF alpha acting on TNFR1 promotes breast cancer growth via p42/P44 MAPK, JNK, Akt and NF-kappa B-dependent pathways. 1806 Nov 62

Although nerve growth factor (NGF) promotes survival of neurons, tumor necrosis factor alpha (TNF-alpha) contributes to cell death triggered by NGF depletion, through TNF-alpha receptor (TNFR) 1. In contrast to this effect, TNF-alpha can promote neural cell survival via TNF-alpha receptor TNFR2. Although these findings demonstrate pivotal roles of TNF-alpha and NGF in cell fate decisions, cross-talk between these signaling pathways has not been clarified. We find that NGF can induce TNF-alpha synthesis through the nuclear factor-kappaB transcription factor. This provides a new basis for examining the cross-talk between NGF and TNF-alpha. Inhibition of TNFR2 shows opposite effects on two downstream kinases of NGF, extracellular signal-regulated kinase (Erk) and Akt. It increases Erk activation by NGF, and this increased activation induces differentiation of neuroblastoma cell lines. Reciprocally, inhibition of TNFR2 decreases Akt activation by NGF. Consistent with an essential role of Akt in survival signaling, inhibition of TNF-alpha signaling decreases NGF-dependent survival of neurons from rat dorsal root ganglia. Thus, NGF and NGF-induced TNF-alpha cooperate to activate Akt, promoting survival of normal neural cells. However, the NGF-induced TNF-alpha suppresses Erk activation by NGF, blocking NGF-induced differentiation of neuroblastoma cells. TNFR2 signaling could be a novel target to modulate cell responses to NGF.
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PMID:Tumor necrosis factor alpha regulates responses to nerve growth factor, promoting neural cell survival but suppressing differentiation of neuroblastoma cells. 1809 51

Inhibitor of NF-kappaB (IkappaB) kinase (IKK) and c-Jun NH(2)-terminal kinase (JNK) are stress inducible kinases that critically regulate numerous physiological and pathological processes. Transient activation of the downstream transcription factors NF-kappaB and AP-1, allows for stress inducible, inflammatory and innate immune gene expression programs. However, elevated chronic activity is associated with cancer and chronic inflammatory disease. Despite its relevance to human health, little is known about the molecular mechanisms that control constitutive activity of IKK and JNK. Here, we demonstrate that the serine/threonine kinase PKN1 plays a critical role in regulating constitutive IKK/JNK activity in unstimulated cells and report on the molecular mechanism. We identify TRAF1 as a substrate of PKN1 kinase activity in vitro and in vivo, and show that this phosphorylation event is required for attenuating downstream kinase activities. Furthermore, this silencing was dependent on TNFR2. Mutagenesis of the phospho-acceptor residue in TRAF1 abrogated PKN1-dependent recruitment to TNFR2. Our results suggest a model by which the stoichiometric ratio of TRAF1 and TRAF2 heteromeric complexes associated with TNFR2 control the tonic activity of JNK and IKK. TRAF1 phosphorylation by the ubiquitously expressed kinase PKN1 thereby plays a critical role in the negative regulation of tonic activity of the two central inflammatory signaling pathways.
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PMID:Negative regulation of constitutive NF-kappaB and JNK signaling by PKN1-mediated phosphorylation of TRAF1. 1842 22

Tumor necrosis factor (TNF) and epidermal growth factor (EGF) are key regulators in the intricate balance maintaining intestinal homeostasis. Previous work from our laboratory shows that TNF attenuates ligand-driven EGF receptor (EGFR) phosphorylation in intestinal epithelial cells. To identify the mechanisms underlying this effect, we examined EGFR phosphorylation in cells lacking individual TNF receptors. TNF attenuated EGF-stimulated EGFR phosphorylation in wild-type and TNFR2(-/-), but not TNFR1(-/-), mouse colon epithelial (MCE) cells. Reexpression of wild-type TNFR1 in TNFR1(-/-) MCE cells rescued TNF-induced EGFR inhibition, but expression of TNFR1 deletion mutant constructs lacking the death domain (DD) of TNFR1 did not, implicating this domain in EGFR downregulation. Blockade of p38 MAPK, but not MEK, activation of ERK rescued EGF-stimulated phosphorylation in the presence of TNF, consistent with the ability of TNFR1 to stimulate p38 phosphorylation. TNF promoted p38-dependent EGFR internalization in MCE cells, suggesting that desensitization is achieved by reducing receptor accessible to ligand. Taken together, these data indicate that TNF activates TNFR1 by DD- and p38-dependent mechanisms to promote EGFR internalization, with potential impact on EGF-induced proliferation and migration key processes that promote healing in inflammatory intestinal diseases.
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PMID:Tumor necrosis factor inhibits ligand-stimulated EGF receptor activation through a TNF receptor 1-dependent mechanism. 1846 4

TRAF2 plays a central role in TNF-induced signalling to NF-kappaB and JNK/p38 MAPK. To better understand the molecular mechanisms that mediate this dual function of TRAF2, we performed a yeast two-hybrid screening for TRAF2 interacting proteins using the Sos recruitment system. This resulted in the identification of the E3 ubiquitin ligase Smurf2 as a TRAF2 binding protein. TRAF2 overexpression was shown to trigger Smurf2 ubiquitination and the formation of a TNF-R2/Smurf2 complex. Smurf2 on its turn promoted TNF-R2 ubiquitination and the relocalization of TNF-R2 as well as TRAF2 to a detergent-insoluble cell fraction. This was associated with enhanced TNF-R2-induced JNK activation, whereas TNF-R2-induced NF-kappaB activation remained unaffected. These results suggest an important role for Smurf2 binding to TRAF2 in determining specific signalling outputs of TNF-R2.
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PMID:Smurf2 is a TRAF2 binding protein that triggers TNF-R2 ubiquitination and TNF-R2-induced JNK activation. 1867 42

Tumor necrosis factor (TNF) is an important cytokine with multiple biological effects, including cell growth, differentiation, apoptosis, immune regulation and induction of inflammation. The effects of TNF are mediated by two receptors, TNF-R1 and TNF-R2. The major signal transduction pathways triggered by TNF include those that lead to apoptosis, activation of transcription factor NF-kappa B and protein kinase JNK. This review will discuss the molecular mechanisms of these signaling pathways.
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PMID:Molecular mechanism of signaling by tumor necrosis factor. 1876 70

Tumour necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine produced by circulating monocytes and resident macrophages during acute inflammation and is responsible for a diverse range of signalling events within cells, leading to necrosis or apoptosis. The biologic activities of TNF are mediated by two receptors TNFR1 and TNFR2, although a lot of studies demonstrated that most of the biological activities of TNF-alpha are mediated through TNFR1. In the present study, we want to evaluate the role of TNF-alpha on regulation of in vitro models of inflammation. In particular we used peritoneal macrophages, from TNF-alphaR1 knock out and TNF-alphaR1 wild-type mice, stimulated with LPS 10 microg/ml and IFN-gamma 100 U/ml. Our results showed that the deletion of TNF-alphaR1 gene significantly reduced the degree of (i) MAPK activation, (ii) IkappaB-alpha degradation, (iii) phosphorylation of Ser536 on the NF-kappaB subunit p65 and (iv) iNOS and COX-2 expression. In addition, to confirm the pivotal role of TNF-alpha on regulation of peritoneal macrophages inflammation, we have also investigated the protective effects of infliximab, a TNF-alpha chimeric mouse/human IgG1 antibody against TNF-alpha. As shown in the present study, the cell incubation with infliximab (0.1 microg/ml, 1 microg/ml and 10 microg/ml) significantly leads to a concentration-dependent inhibition of the inflammatory mediators above described. In conclusion, our study demonstrates that pharmacological and genetic inhibition of the TNF/TNFR1 binding reduce the degree of macrophages inflammation caused by LPS/IFN-gamma stimulation.
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PMID:Effects of genetic and pharmacological inhibition of TNF-alpha in the regulation of inflammation in macrophages. 1945 Jun 84

A 24-h treatment with the cytokine tumor necrosis factor-alpha (TNF-alpha) suppresses transcription of E-box-driven clock genes (D-site albumin promoter binding protein, Dbp; Tyrotroph embryonic factor, Tef ; Hepatic leukemia factor, Hlf; Period homolog to Drosophila 1/2/3, Per1, Per2, and Per3) by yet unknown molecular mechanisms. The attenuation of clock genes has been suggested as a putative cause for the development of sickness behavior syndrome in infectious and autoimmune diseases. Here, the authors studied the effect of TNF-alpha at early time points (<3 h) on intracellular signaling events and clock gene expression in fibroblasts. Interaction of TNF-alpha with TNFR1 (Tnfrsf1a , CD120a, p55), but not TNFR2 (Tnfrsf1b, CD120b , p75), leads to fast downregulation of gene expression of Dbp and upregulation of negative regulators of the molecular clock, Per1 and Per2, Cryptochrome-1 (Cry1), and Differentiated embryo chondrocytes-1 (Dec1). Since the decrease of Dbp is also observed in cells deficient for Per1/Per2, Cry1/Cry2 , or Dec1, these genes are unlikely to be responsible for inhibition of Dbp. The early effect of TNF-alpha on the clock gene Per1 is dependent on p38, mitogen-activated protein kinase (MAPK), and/or calcium signaling, whereas the effect on Dbp is independent of p38 MAPK, but also involves calcium signaling. Both genes remain unaffected by the NF-kappaB and AP-1 pathway. Taken collectively these data show p38 MAPK- and calcium-dependent TNFR1-mediated transient increase of the negative regulator Per1 and an independent decrease of Dbp.
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PMID:Clock gene modulation by TNF-alpha depends on calcium and p38 MAP kinase signaling. 1962 30

Tumor necrosis factor (TNF) elicits its biological activities by stimulation of two receptors, TNFR1 and TNFR2, both belonging to the TNF receptor superfamily. Whereas TNFR1-mediated signal transduction has been intensively studied and is understood in detail, especially with respect to activation of the classical NFkappaB pathway, cell death induction, and MAP kinase signaling, TNFR2-associated signal transduction is poorly defined. Here, we demonstrate in various tumor cell lines and primary T-cells that TNFR2, but not TNFR1, induces activation of the alternative NFkappaB pathway. In accord with earlier findings demonstrating that only membrane TNF, but not soluble TNF, properly activates TNFR2, we further show by use of TNFR1- and TNFR2-specific mutants of soluble TNF and membrane TNF that soluble ligand trimers fail to activate the alternative NFkappaB pathway. In accord with the known inhibitory role of TRAF2 in the alternative NFkappaB pathway, TNFR2-, but not TNFR1-specific TNF induced depletion of cytosolic TRAF2. Thus, we identified activation of the alternative NFkappaB pathway as a TNF signaling effect that can be specifically assigned to TNFR2 and membrane TNF.
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PMID:Membrane tumor necrosis factor (TNF) induces p100 processing via TNF receptor-2 (TNFR2). 2003 84

TNF is a potent cytokine with an important role in the regulation of a multitude of cellular responses and in coordinating immune and inflammatory reactions. TNF exerts its effects by binding to the TNFR1- and TNFR2-specific cell surface receptors, which activate a number of intracellular signaling cascades including the nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinase pathways. Activation of NF-kappaB mediates many of the functions of TNF by transmitting information from the cell surface TNF receptors to the nucleus, where it coordinates a gene expression program that allows the cell to survive and elicit its responses. The intimate interplay of TNF with the NF-kappaB signaling pathway is highlighted by results obtained in transgenic and knockout mice with defects in NF-kappaB signaling components, where TNF has been shown to contribute to different pathologies observed in these mice. This chapter focuses on the function of TNF in pathologies induced by NF-kappaB deficiency and discusses the implications of these findings for our understanding of inflammatory diseases.
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PMID:Role of TNF in pathologies induced by nuclear factor kappaB deficiency. 2017 88


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