Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endotoxic lipopolysaccharide (LPS) is a proinflammatory agonist produced by gram-negative bacteria and a contributor to the majority of the 400,000 septic shock cases recorded annually in US hospitals. The primary target cells for LPS are monocytes and macrophages. Their response consists of massive production of proinflammatory cytokines, reactive oxygen- and nitrogen-intermediates, procoagulants, and cell adhesion molecules. In turn, expression of these LPS-responsive factors contributes to collapse of the circulatory system, to disseminated intravascular coagulation, and to a 30% mortality rate. A common intracellular mechanism responsible for the expression of septic shock genes in monocytes and macrophages involves the activation of NF-kappaB. This transcription factor is regulated by a family of structurally related inhibitors including IkappaBalpha, IkappaBbeta, and IkappaBepsilon, which trap NF-kappaB in the cytoplasm. In this report, the investigators show that LPS derived from different gram-negative bacteria activates cytokine-responsive IkappaB kinases containing catalytic subunits termed IKKalpha (IKK1) and IKKbeta (IKK2). The kinetics of IKKalpha and IKKbeta activation in LPS-stimulated human monocytic cells differ from that recorded on their stimulation with tumor necrosis factor-alpha, thereby implying a distinct activation mechanism. LPS-activated IKK complexes phosphorylate all 3 inhibitors of NF-kappaB: IkappaBalpha, IkappaBbeta, and IkappaBepsilon. Moreover, LPS activates IKKbeta preferentially, relative to IKKalpha. Thus, IKK complex constitutes the main intracellular target for LPS-induced NF-kappaB signaling to the nucleus in human monocytic cells to activate genes responsible for septic shock.
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PMID:IkappaB kinase complex is an intracellular target for endotoxic lipopolysaccharide in human monocytic cells. 1047 96

NF-kappaB is a critical mediator of macrophage inflammatory responses, but its role in regulating macrophage survival has yet to be elucidated. Here, we demonstrate that constitutive NF-kappaB activation is essential for macrophage survival. Blocking the constitutive activation of NF-kappaB with pyrrolidine dithiocarbamate or expression of IkappaBalpha induced apoptosis in macrophagelike RAW 264.7 cells and primary human macrophages. This apoptosis was independent of additional death-inducing stimuli, including Fas ligation. Suppression of NF-kappaB activation induced a time-dependent loss of mitochondrial transmembrane potential (DeltaPsi(m)) and DNA fragmentation. Examination of initiator caspases revealed the cleavage of caspase 9 but not caspase 8 or the effector caspase 3. Addition of a general caspase inhibitor, z-VAD. fmk, or a specific caspase 9 inhibitor reduced DNA fragmentation but had no effect on DeltaPsi(m) collapse, indicating this event was caspase independent. To determine the pathway leading to mitochondrial dysfunction, analysis of Bcl-2 family members established that only A1 mRNA levels were reduced prior to DeltaPsi(m) loss and that ectopic expression of A1 protected against cell death following inactivation of NF-kappaB. These data suggest that inhibition of NF-kappaB in macrophages initiates caspase 3-independent apoptosis through reduced A1 expression and mitochondrial dysfunction. Thus, constitutive NF-kappaB activation preserves macrophage viability by maintaining A1 expression and mitochondrial homeostasis.
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PMID:Macrophages require constitutive NF-kappaB activation to maintain A1 expression and mitochondrial homeostasis. 1107 86

The NFkappaB transcription factors can both promote cell survival and induce apoptosis depending on cell type and context. Neuroblastoma (NB) cells display two predominant culture phenotypes identified as N- and S-types. Malignant S-type cells express neither high levels of MYCN nor Bcl-2, suggesting that other survival mechanisms are important. We characterized NFkappaB activity in S-type cells and determined its role in their survival. S-type lines (SH-EP1 and SK-N-AS) were treated with pyrrolidine dithiocarbamate (PDTC), a NFkappaB inhibitor, or l-1-tosylamido-2-phenylethyl chloromethyl ketone (TPCK), a serine protease inhibitor that blocks IkappaBalpha degradation. Both agents induced cell death, suggesting that constitutive NFkappaB activity is required for survival. The transient expression of a super-repressor IkappaBalpha mutant killed S-type cells. The inhibition of NFkappaB produced an apoptotic response characterized by the collapse of the mitochondrial transmembrane electrochemical gradient, caspase-9 activation, and apoptotic DNA changes. Constitutive NFkappaB DNA binding activity specifically involving p65 and p50 was demonstrated in S- but not N-type cells by electromobility supershift and gene reporter assays. This study demonstrates a role for NFkappaB in the survival of S-type NB tumor cells and suggests that NFkappaB activity and function differ according to NB tumor cell phenotype.
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PMID:Constitutively active NFkappa B is required for the survival of S-type neuroblastoma. 1219 14

Skeletal muscle atrophy is a common debilitating feature of many systemic diseases, including cancer. Here we examined the effects of inducing expression of an oncogenic version of the Met receptor (Tpr-Met) in terminally differentiated skeletal muscle. A responder mouse containing the Tpr-Met oncogene and GFP (green fluorescent protein) as a reporter was crossed with a transactivator mouse expressing tTA under the control of the muscle creatine kinase promoter. Tpr-Met induction during fetal development and in young adult mice caused severe muscle wasting, with decreased fiber size and loss of myosin heavy chain protein. Concomitantly, in the Tpr-Met-expressing muscle the mRNA of the E3 ubiquitin ligases atrogin-1/MAFbx, MuRF1, and of the lysosomal protease cathepsin L, which are markers of skeletal muscle atrophy, was significantly increased. In the same muscles phosphorylation of the Met downstream effectors Akt, p38 MAPK, and IkappaBalpha was higher than in normal controls. Induction of Tpr-Met in differentiating satellite cells derived from the double transgenics caused aberrant cell fusion, protein loss, and myotube collapse. Increased phosphorylation of Met downstream effectors was also observed in the Tpr-Met-expressing myotubes cultures. Treatment of these cultures with either a proteasomal or a p38 inhibitor prevented Tpr-Met-mediated myotube breakdown, establishing accelerated protein degradation consequent to inappropriate activation of p38 as the major route for the Tpr-Met-induced muscle phenotype.
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PMID:Conditional activation of MET in differentiated skeletal muscle induces atrophy. 1719

Because tumor necrosis factor-alpha (TNF-alpha) is well-known to induce inflammatory responses, thus its clinical use is limited in cancer treatment. Rosmarinic acid (RA), a naturally occurring polyphenol flavonoid, has been reported to inhibit TNF-alpha-induced NF-kappaB activation in human dermal fibroblasts. However, the precise mechanisms of RA have not been well elucidated in TNF-alpha-mediated anti-cancer therapy. In this study, we found that RA treatment significantly sensitizes TNF-alpha-induced apoptosis in human leukemia U937 cells through the suppression of nuclear transcription factor-kappaB (NF-kappaB) and reactive oxygen species (ROS). Activation of caspases in response to TNF-alpha was markedly increased by RA treatment. However, pretreatment with the caspase-3 inhibitor, z-DEVD-fmk, was capable of significantly restoring cell viability in response to combined treatment. RA also suppressed NF-kappaB activation through inhibition of phosphorylation and degradation of IkappaBalpha, and nuclear translocation of p50 and p65. This inhibition was correlated with suppression of NF-kappaB-dependent anti-apoptotic proteins (IAP-1, IAP-2, and XIAP). RA treatment also normalized TNF-alpha-induced ROS generation. Additionally, ectopic Bcl-2 expressing U937 reversed combined treatment-induced cell death, cytochrome c release into cytosol, and collapse of mitochondrial potential. These results demonstrated that RA inhibits TNF-alpha-induced ROS generation and NF-kappaB activation, and enhances TNF-alpha-induced apoptosis.
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PMID:Rosmarinic acid sensitizes cell death through suppression of TNF-alpha-induced NF-kappaB activation and ROS generation in human leukemia U937 cells. 1961 38

Malignant gliomas are characterized by invasive and infiltrative behavior that generally involves the destruction of normal brain tissue. Strategies to treat infiltrating gliomas, such as chemotherapy and gene therapy, have remained largely unsuccessful. The infiltrative nature of gliomas can be attributed largely to proteases, which include serine, metallo- and cysteine- proteases. Our previous work and that of others strongly suggest a relationship between the expression of uPAR, MMP-9, and MMP-2; this relationship is generally indicative of the infiltrative phenotype of gliomas. In the present study, we have demonstrated that the RNAi-mediated downregulation of MMP-2 induces apoptosis in the 4910 human glioma xenograft cell line. Using Western blot analysis, we observed that caspase-8 levels increased in MMP-2-downregulated cells whereas TRADD and TRAF-2 levels decreased. Further, NIK levels increased in MMP-2-downregulated cells. To determine the nuclear localization of AIF and IkappaBalpha, we analyzed the levels of AIF, IkappaBalpha and pIkappaBalpha in the cytosolic and nuclear fractions of MMP-2-downregulated cells. Western blot analysis revealed that MMP-2 downregulation resulted in the translocation of AIF to the nucleus and also inhibited the nuclear localization of pIkappaBalpha. To confirm the involvement of AIF, we performed FACS analysis to determine the integrity of the mitochondrial membrane using the MitoPT method. FACS analysis showed that the downregulation of MMP-2 caused a collapse in the mitochondrial cell membrane. Immunolocalization of AIF revealed that in MMP-2-downregulated cells, AIF translocates to the nucleus, thereby enabling the induction of apoptosis. RT-PCR analysis revealed that caspase-8 was overexpressed 57-fold, whereas p73 was downregulated 28-fold. Evidence of apoptosis was determined by TUNEL assay and visualization of nuclear fragmentation by DAPI staining. In summary, it is evident from our results that MMP-2 downregulation induces caspase-8 and AIF-mediated apoptosis and, as such, shows potential for glioma therapy.
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PMID:RNAi-mediated downregulation of MMP-2 activates the extrinsic apoptotic pathway in human glioma xenograft cells. 1972 22