Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042384 (vasculitis)
 20,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anti-neutrophil cytoplasm autoantibodies (ANCA) are implicated in the pathogenesis of systemic vasculitis. Intact ANCA IgG activate superoxide generation in cytokine-primed neutrophils after binding their antigens and co-engaging Fcgamma receptors (FcgammaR). The contribution of antigen binding via ANCA F(ab')(2) fragments to signaling has been unclear. This study shows that both ANCA IgG and F(ab')(2) fragments of ANCA IgG induce significant GTPase activity, which could be blocked with pertussis toxin and anti-G(i) protein antibodies. Pertussis toxin inhibited ANCA IgG-induced superoxide generation but was without effect on superoxide production after conventional FcgammaR ligation. ANCA F(ab')(2) fragments did not induce superoxide generation. ANCA IgG activated PI 3-kinase-generating PIP(3), activated protein kinase B (PKB), and p21(ras); activation of each mediator was inhibited with pertussis toxin, but PI3K and PKB were not activated by ANCA IgG F(ab')(2) fragments. Intact ANCA IgG induced tyrosine phosphorylation, whereas F(ab')(2) fragments did not, and ANCA IgG-mediated superoxide generation was inhibited with genistein. Both genistein and pertussis toxin together completely abrogated the ANCA-induced oxidative burst. Genistein also inhibited ANCA IgG-induced PIP(3) generation and p21(ras) activation. These data implicate a novel ANCA IgG stimulated signaling pathway that involves both F(ab')(2)-mediated antigen binding and Fc-mediated FcgammaR ligation in cooperative interactions between G(i) proteins and tyrosine kinases that facilitates activation of downstream mediators.
 ...
PMID:Activation of the G(i) heterotrimeric G protein by ANCA IgG F(ab')2 fragments is necessary but not sufficient to stimulate the recruitment of those downstream mediators used by intact ANCA IgG. 1259 2

Antineutrophil cytoplasm antibodies (ANCA) are implicated in the pathogenesis of systemic vasculitis. ANCA are directed against antigens expressed on the surface of cytokine-primed neutrophils. It was shown previously that whole IgG ANCA and its fraction antigen binding [F(ab')(2)] fragment can activate the GTPase p21(ras). This study shows a functional involvement of this molecule in the ANCA activation of neutrophils by inhibiting the production of superoxide with farnesylthiosalicylic acid. Using the ras activation assay, farnesylthiosalicylic acid inhibits p21(ras) binding to its substrate at comparable concentrations to those seen for superoxide inhibition. It is also shown that activation of p21(ras) by ANCA is transient, peaking at 5 to 10 min and returning to baseline by 30 min. The use of ras isoform-specific antibodies in Western blots established, for the first time, that Harvey-ras is not present in human neutrophils, but both Kirsten-ras (K-ras) and Neuronal-ras are. Stimulation with ANCA is able to differentially activate K-ras without effects on neuronal-ras. The activation of p21(ras) by ANCA and its F(ab')(2) is prevented by inhibition of both Src kinases and phosphatidylinositol-3-kinase, indicating a cooperative role for both molecules in the G protein pathway activated by ANCA F(ab')(2) upstream of p21(ras). It is concluded that ANCA selectively activates K-ras during induction of a respiratory burst via pathways involving multiple upstream kinases.
 ...
PMID:Characterization of the regulation and functional consequences of p21ras activation in neutrophils by antineutrophil cytoplasm antibodies. 1554 65

PR3, also called myeloblastin, is a neutrophil serine protease that promotes myeloid cell proliferation by cleaving the cyclin-dependent kinase inhibitor p21(cip1/waf1). In addition, it is the target of ANCA in GPA, a necrotizing vasculitis. Anti-PR3 ANCA binding to membrane-expressed PR3 triggers neutrophil activation, potentiating vascular inflammation. This study performed in RBL cells identifies the structural motifs of PR3 membrane anchorage and examines its impact on PR3 proinflammatory and proliferative functions. With the use of MD simulations and mutagenesis, we demonstrate that the mutations of four hydrophobic (F180, F181, L228, F229) or four basic (R193, R194, K195, R227) amino acids abrogated PR3 membrane anchorage. The hydrophobic patch-deficient PR3 mutant (PR34H4A) was still able to cleave the synthetic substrate Boc-Ala-Pro-Val in cell lysates. However, in contrast to WT PR3, PR34H4A was not expressed at the plasma membrane after degranulation and failed to cleave extracellular fibronectin, was not externalized after apoptosis and did not impair macrophage phagocytosis of apoptotic cells, did not promote myeloid cell proliferation and failed to cleave p21/waf1. PR3 membrane insertion appears to be pivotal for its proinflammatory activities, such as extracellular proteolysis and impairment of apoptotic cell clearance, but also for myeloid cell proliferation. Targeting membrane-associated PR3 might constitute a novel, anti-inflammatory therapeutic strategy in inflammatory disease especially in vasculitis, but this approach has to be validated in mature neutrophils.
 ...
PMID:Molecular analysis of the membrane insertion domain of proteinase 3, the Wegener's autoantigen, in RBL cells: implication for its pathogenic activity. 2182 19

Dermatologic toxicities associated with anticancer-targeted therapy include hand-foot skin reactions, vasculitis, cutaneous epithelial proliferations, such as keratosis, keratoacanthoma, and invasive squamous cell carcinoma. In this case report, we describe alterations of tumor morphology and patterns of cyclin-dependent kinase inhibitor (CDKI) expression in a patient who received GSK2118436, a second-generation RAF inhibitor, for stage IV (M1c) metastatic melanoma. To explore the effects of GSK2118436 on the expression patterns of CDKI (p16, p21, p27, p57), we immunohistochemically evaluated in vivo melanoma cells pre- and posttreated with GSK2118436. After GSK2118436 treatment, the melanoma cells decreased in size and demonstrated hyperchromatic nuclei and indistinct nucleoli. p16 was strongly expressed in the cytoplasm of pretreated melanoma cells and in the nucleus and cytoplasm in posttreated melanoma cells. Expression of both p27 (nucleus) and p57 (cytoplasm) was increased in posttreated melanoma cells and no significant difference in p21 expression was noted in either pre- or posttreated tumor cells. These findings may help explain the molecular mechanisms by which tumor cells retain the ability to proliferate. The persistent activation of pro-oncogenic activities of CDKI (eg, p27 and p57) and/or compartmentalization of p16 in cytoplasm or nucleus may allow tumor cells to bypass BRAF-induced senescence mechanisms. Furthermore, awareness of changes in tumor morphology after treatment with RAF inhibitors may be helpful in histologic evaluation of the spectrum of dermatologic toxicity, which may occur on targeted therapy.
 ...
PMID:Changes in tumor morphology and cyclin-dependent kinase inhibitor expression in metastatic melanoma treated with selective second-generation BRAF inhibitor. 2287 67

BACKGROUND Overexpression of p53, p21, and caspase-3 promotes apoptosis of vascular smooth muscle cells. However, the mechanisms that lead to apoptosis of coronary artery smooth muscle cells (CASMCs) is unclear in Kawasaki disease (KD). This study investigated involvement of p53, p21, and caspase-3 in the apoptosis of CASMCs from a Kawasaki vasculitis mouse model. MATERIAL AND METHODS The Kawasaki vasculitis mouse model with coronary artery lesions was generated via administration of Lactobacillus casei cell wall extract. In 2 groups of mice (healthy control and KD vasculitis mice), the levels of p53, p21, and caspase-3 protein in the root of the coronary artery were evaluated via immunohistochemistry. Receiver operating characteristic curves were plotted for determination of area under the curve, 95% confidence interval, sensitivity, specificity, and cutoff values for the ability of p53, p21, and caspase-3 expression to predict CASMC apoptosis and coronary artery lesion formation in KD vasculitis mice. RESULTS Compared with healthy mice, KD vasculitis mice had a significantly higher apoptosis index and upregulated p53, p21, and caspase-3 expression. Also, the immunoreactive score for caspase-3 was positively correlated with the immunoreactivity scores for p53 and p21. The optimal cutoff values for p53, p21, and caspase-3 expression for predicting the presence of coronary artery lesions were 4.15, 4.18, and 4.22, respectively. CONCLUSIONS Upregulated levels of p53, p21, and caspase-3 promoted apoptosis of CASMCs in KD vasculitis mice. Thus, the levels of p53, p21, and caspase-3 may serve as valuable predictors of coronary artery lesion formation in KD.
 ...
PMID:Involvement of p53, p21, and Caspase-3 in Apoptosis of Coronary Artery Smooth Muscle Cells in a Kawasaki Vasculitis Mouse Model. 3282 Jan 44