Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (AngII) functions as a stress hormone under conditions of stretch, pressure and injury to stimulate smooth muscle cell migration and proliferation. Since the cellular response to stress is mediated in part by the transcription factor NF-kappaB, the relationship between AngII and NF-kappaB was investigated. Our study revealed that AngII promoted a dose-dependent and transient phosphorylation of the regulatory IkappaBalpha protein in smooth muscle cells from porcine coronary artery, with concomitant nuclear translocation of NF-kappaB and increased binding to a kappaB promoter element. Both nuclear translocation and kappaB-element binding were prevented by the AT(1) receptor antagonist losartan. The role of NF-kappaB in AngII-dependent smooth muscle cell migration and proliferation was then assessed. Inhibitors of NF-kappaB nuclear translocation (phenethyl caffeiate) and IkappaB phosphorylation (Bay 11-7085) effectively arrested both AngII-dependent DNA synthesis and migration. These results were confirmed with SN50, a highly selective peptide inhibitor of NF-kappaB activation. Phenethyl caffeiate also prevented the phosphorylation of cdk2 and Rb, indicating NF-kappaB was required for G1/S transition. The target of NF-kappaB inhibition was identified as cyclin E, since induction of this gene, but not cyclin D1, was suppressed by phenethyl caffeiate. We subsequently examined the relationship between NF-kappaB and neointimal formation in response to angioplasty-induced injury, a process susceptible to inhibition by losartan. Both phenethyl caffeiate and Bay 11-7085 blocked neointimal hyperplasia in organ culture following balloon angioplasty. These data indicate NF-kappaB is an important mediator of intracellular signalling by AngII under normal physiological conditions, and following vascular injury.
J Mol Cell Cardiol 2002 Dec
PMID:NF-kappaB activation is essential for angiotensin II-dependent proliferation and migration of vascular smooth muscle cells. 1250 59

The activation of the NF-kappaB family of transcription factors plays a crucial role in oncogenesis. The IkappaB family has the ability to retain the NF-kappaB in an inactive complex in the cytoplasm. Recently, mutations of the IkappaBalpha gene were found in Hodgkin's lymphoma, which allows NF-kappaB proteins to translocate into the nucleus in an active form. In this report, we describe a mutational analysis of IkappaBalpha for primary tumor cells obtained from patients with a variety of hematologic malignancies (acute myelogenous leukemia, chronic myelogenous leukemia, myelodysplastic syndrome, hairy cell leukemia, adult T-cell leukemia, and mantle cell lymphoma) as well as 15 leukemia, lymphoma, and myeloma cell lines (HL60, U937, HEL, K562, NALM1, Jurkat, JM, MOLT4, Raji, KS1, OKM2T, OKM3T, F6T, Su9T01, and C2-2). RT-PCR, followed by direct sequencing, was performed and all samples expressed IkappaBalpha. One missense mutation was identified in a primary effusion lymphoma cell line, KS1. However, NF-kappaB (p65) protein was absent from the nucleus of KS1 immunohistochemically, suggesting that the mutation did not alter the function of IkappaBalpha in this case. Taken together, although it is not clear whether normal IkappaBalpha protein was expressed in hematologic malignancies, mutations of IkappaBalpha could be rare events in these diseases, except for Hodgkin's lymphoma. Alterations of other members of NF-kappaB/ IkappaB family proteins might act on the development of hematologic malignancies.
Int J Mol Med 2003 Feb
PMID:Mutational analysis of IkappaBalpha in hematologic malignancies. 1252 85

TNF-related apoptosis-inducing ligand (TRAIL/Apo- 2L), a newly identified member of the TNF family promotes apoptosis by binding to the transmembrane receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). TRAIL known to activate NF-kappaB in number of tumor cells including A549 (wt p53) and NCI-H1299 (null p53) lung cancer cells exerts relatively selective cytotoxic affects to the human tumor cell lines without much effect on the normal cells. We set out to identify an agent that would sensitize lung cancer cells to TRAIL-induced apoptosis through inhibition of NF-kappaB activation. We found that triptolide, an oxygenated diterpene extracted and purified from the Chinese herb Tripterygium wilfordii sensitized A549 and NCI-H1299 cells to TRAIL-induced apoptosis through inhibition of NF-kappaB activation. Pretreatment with MG132 which is a well-known NF-kappaB inhibitor by blocking degradation of IkappaBalpha also greatly sensitized lung cancer cells to TRAIL-induced apoptosis. Triptolide did not block DNA binding of NF-kappaB activated by TRAIL as in the case of TNF-alpha. It has been already proven that triptolide blocks transactivation of p65 which plays a key role in NF-kappaB activation. These observations suggest that triptolide may be a potentially useful drug to enhance TRAIL-induced tumor killing in lung cancer.
Exp Mol Med 2002 Dec 31
PMID:Triptolide sensitizes lung cancer cells to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis by inhibition of NF-kappaB activation. 1252 88

Anandamide (arachidonoylethanolamine, AEA), an endogenous agonist for both the cannabinoid CB(1) receptor and the vanilloid VR1 receptor, elicits neurobehavioral, anti-inflammatory, immunomodulatory, and proapoptotic effects. Because of the central role of nuclear factor-kappaB (NF-kappaB) in the inflammatory process and the immune response, we postulated that AEA might owe some of its effects to the suppression of NF-kappaB. This study shows that AEA inhibits tumor necrosis factor-alpha (TNFalpha)-induced NF-kappaB activation by direct inhibition of the IkappaB kinase (IKK)beta and, to a lesser extent, the IKKalpha subunits of kappaB inhibitor (IkappaB) kinase complex, and that IKKs inhibition by AEA correlates with inhibition of IkappaBalpha degradation, NF-kappaB binding to DNA, and NF-kappaB-dependent transcription in TNFalpha-stimulated cells. AEA also prevents NF-kappaB-dependent reporter gene expression induced by mitogen-activated protein kinase kinase kinase and NF-kappaB-inducing kinase. The NF-kappaB inhibitory activity of AEA was independent of CB(1) and CB(2) activation in TNFalpha-stimulated 5.1 and A549 cell lines, which do not express vanilloid receptor 1, and was not mediated by hydrolytic products formed through the activity of the enzyme fatty acid amide hydrolase. Chemical modification markedly affected AEA inhibitory activity on NF-kappaB, suggesting rather narrow structure-activity relationships and the specific interaction with a molecular target. Substitution of the alkyl moiety with less saturated fatty acids generally reduced or abolished activity. However, replacement of the ethanolamine "head" with a vanillyl group led to potent inhibition of TNFalpha-induced NF-kappaB-dependent transcription. These findings provide new mechanistic insights into the anti-inflammatory and proapoptotic activities of AEA, and should foster the synthesis of improved analogs amenable to pharmaceutical development as anti-inflammatory agents.
Mol Pharmacol 2003 Feb
PMID:Anandamide inhibits nuclear factor-kappaB activation through a cannabinoid receptor-independent pathway. 1252 15

The transcription factor NF-kappaB is overexpressed or constitutively activated in many cancer cells, where it induces expression of antiapoptotic genes correlating with resistance to anticancer therapies. Small molecules that inhibit the NF-kappaB signaling pathway could therefore be used to induce apoptosis in NF-kappaB-overexpressing tumors and potentially serve as anticancer agents. We found that retinoid antagonist MX781 inhibited the activation of NF-kappaB-dependent transcriptional activity in different tumor cell lines. MX781 was able to completely inhibit tumor necrosis factor alpha-mediated activation of IkappaB kinase (IKK), the upstream regulator of NF-kappaB. Inhibition of IKK activity resulted from direct binding of MX781 to the kinase, as demonstrated by in vitro inhibition studies. Two other molecules, MX3350-1 and CD2325, which are retinoic acid receptor gamma-selective agonists, were capable of inhibiting IKK in vitro, although they exerted variable inhibition of IKK and NF-kappaB activities in intact cells in a cell type-specific manner. However, N-(4-hydroxyphenyl)-retinamide, another apoptosis-inducing retinoid, and retinoic acid as well as other nonapoptotic retinoids did not inhibit IKK. Inhibition of IKK by the retinoid-related compounds and other small molecules correlated with reduced cell proliferation and increased apoptosis. Reduced cell viability was also observed after overexpression of an IKKbeta kinase-dead mutant or the IkappaBalpha superrepressor. The induction of apoptosis by the retinoid-related molecules that inhibited IKK was dependent on caspase activity but independent of the retinoid receptors. Thus, the presence of an excess of retinoic acid or a retinoid antagonist did not prevent the inhibition of IKK activation by MX781 and CD2325, indicating a retinoid receptor-independent mechanism of action.
Mol Cell Biol 2003 Feb
PMID:Inhibition of IkappaB kinase by a new class of retinoid-related anticancer agents that induce apoptosis. 1252 10

Notch and NFkappaB pathways are key regulators of numerous cellular events such as proliferation, differentiation, or apoptosis. In both pathways, association of effector proteins with nuclear corepressors is responsible for their negative regulation. We have previously described that expression of a p65-NFkappaB mutant that lacks the transactivation domain (p65DeltaTA) induces cytoplasmic translocation of N-CoR leading to a positive regulation of different promoters. Now, we show that cytoplasmic sequestration of p65 by IkappaBalpha is sufficient to both translocate nuclear corepressors SMRT/N-CoR to the cytoplasm and upregulate transcription of Notch-dependent genes. Moreover, p65 and IkappaBalpha are able to directly bind SMRT, and this interaction can be inhibited in a dose-dependent manner by the CREB binding protein (CBP) coactivator and after TNF-alpha treatment, suggesting that p65 acetylation is modulating this interaction. In agreement with this, TNF-alpha treatment results in downregulation of the Hes1 gene. Finally, we present evidence on how this mechanism may influence cell differentiation in the 32D myeloid progenitor system.
Mol Biol Cell 2003 Feb
PMID:IkappaBalpha and p65 regulate the cytoplasmic shuttling of nuclear corepressors: cross-talk between Notch and NFkappaB pathways. 1258 49

Human labour is associated with persistently increased nuclear factor kappa B (NF-kB) activity in amnion. In this study we have shown that this involves only the p65 and p50 NF-kB subunits and is associated with an increase in the expression of p65 (P < 0.05), and of the NF-kB binding proteins IkBa, IkBb-1 and IkBb-2 (P < 0.05). Interleukin-1b stimulation leads to rapid degradation and resynthesis of IkBa within 2 h, and a decrease in IkBb-1 without a return to full expression by 2 h, but has little effect upon IkBb-2. IkBb-2 was found in both the cytosolic and nuclear protein fractions. These findings demonstrate that persistently increased NF-kB activity in amnion occurs despite increased expression of the inhibitory IkBa protein and is not mediated by persistant I-kappa kinase activity or inhibition of IkBa synthesis. The increased expression and nuclear localization of IkBb-2 suggests that its function may be to protect NF-kB from inactivation by IkBa and to maintain NF-kB-mediated gene transcription.
Mol Hum Reprod 2003 Apr
PMID:The effects of labour and of interleukin 1 beta upon the expression of nuclear factor kappa B related proteins in human amnion. 1265 3

Recent studies have revealed a positive correlation between astrocyte apoptosis and rapid disease progression in persons with neurodegenerative diseases. Glycogen synthase kinase 3beta (GSK-3beta) is a molecular regulator of cell fate in the central nervous system and a target of the phosphatidylinositol 3-kinase (PI-3K) pathway. We have therefore examined the role of the PI-3K pathway, and of GSK-3beta, in regulating astrocyte survival. Our studies indicate that inhibition of PI-3K leads to apoptosis in primary cortical astrocytes. Furthermore, overexpression of a constitutively active GSK-3beta mutant (S9A) is sufficient to cause astrocyte apoptosis, whereas an enzymatically inactive GSK-3beta mutant (K85M) has no effect. In light of reports on the interplay between GSK-3beta and nuclear factor kappaB (NF-kappaB), and because of the antiapoptotic activity of NF-kappaB, we examined the effect of GSK-3beta overexpression on NF-kappaB activation. These experiments revealed strong inhibition of NF-kappaB activation in astrocytes upon overexpression of the S9A, but not the K85M, mutant of GSK-3beta. This was accompanied by stabilization of the NF-kappaB-inhibitory protein, IkappaBalpha and down-regulation of IkappaB kinase (IKK) activity. These findings therefore implicate GSK-3beta as a regulator of NF-kappaB activation in astrocytes and suggest that the pro-apoptotic effects of GSK-3beta may be mediated at least in part through the inhibition of NF-kappaB pathway.
Mol Cell Biol 2003 Jul
PMID:Glycogen synthase kinase 3beta-mediated apoptosis of primary cortical astrocytes involves inhibition of nuclear factor kappaB signaling. 1280 4

Rel/nuclear factor-kappaB (NF-kappaB) transcription factors control a variety of cellular processes, such as cell growth and apoptosis, and are continually activated in many human diseases, including chronic inflammatory diseases and cancer. Jesterone dimer (JD) is a synthetic derivative of the natural fungal metabolite jesterone, and JD has previously been shown to be cytotoxic in select tumor cell lines. In this report, we demonstrate that JD is a potent inhibitor of the activation of transcription factor NF-kappaB. Namely, JD inhibits tumor necrosis factor-alpha-induced activation of NF-kappaB in mouse 3T3 and human HeLa cells. JD seems to block the induction of the NF-kappaB pathway by inhibiting the inhibitor of kappaB kinase (IKK); that is, treatment of cells with JD blocks phosphorylation of IkappaBalpha, inhibits the activity of a constitutively active form of the IKKbetacatalytic subunit, and converts IKKbetato stable high molecular mass forms. Like JD, a JD-related epoxyquinoid (isotorreyanic acid) inhibits activation of NF-kappaB at 20 microM, whereas several other epoxyquinoids that are related to JD, including its parent compound jesterone, do not block activation of NF-kappaB at this concentration. Finally, JD inhibits both proliferation and DNA binding by REL-containing complexes in the human lymphoma SUDHL-4 cell line, and JD activates caspase-3 activity in these cells. In summary, these results suggest that JD induces apoptosis in tumor cells through a mechanism that involves the inhibition of Rel/NF-kappaB activity and demonstrate the usefulness of assessing the bioactivity of synthetic derivatives of natural products.
Mol Pharmacol 2003 Jul
PMID:Jesterone dimer, a synthetic derivative of the fungal metabolite jesterone, blocks activation of transcription factor nuclear factor kappaB by inhibiting the inhibitor of kappaB kinase. 1281 68

Transcription factors within a family usually share the ability to recognize similar or identical consensus sites. For example, the five mammalian NF-kappaB/Rel proteins generate more than 12 dimers recognizing 9-11 nucleotide kappaB sites. Each dimer selectively regulates a few target promoters; however, several genes are redundantly induced by more than one dimer. Whether this property simply generates redundancy in target gene activation or underlies more complex regulatory mechanisms is an open issue. We show here that during dendritic cell maturation, rapidly activated dimers (e.g., p50/RelA) bound to a subset of target promoters are gradually replaced by slowly activated dimers (e.g., p52/RelB). Since the dimers have different transcriptional activity at each promoter, the dimer exchange allows fine tuning of the response over time. Further, due to the insensitivity of p52/RelB to the NF-kappaB inhibitors, the IkappaBs, dimer exchange contributes to sustained activation of selected NF-kappaB targets in spite of the resynthesis of IkappaBalpha.
Mol Cell 2003 Jun
PMID:Modulation of NF-kappaB activity by exchange of dimers. 1282 Sep 69


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