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)

Malignant mesothelioma (MM) is an asbestos-associated cancer that is increasing in incidence worldwide and is refractory to conventional therapy. MM cells are potent sources of a number of cytokines, some of which have recently been shown to be directly involved in the aggressive growth and spread of MM tumors. Emerging data also suggest involvement of MM-derived cytokines in systemic paraneoplastic syndromes including immunosuppression, thrombocytosis, cachexia, amyloidosis, and hypoglycemia. Additional characterization of the expression of cytokines and cytokine receptors in situ in MM tumors may provide a more complete picture of the autocrine and paracrine processes which occur in MM. Improved therapy of MM, particularly cytokine-based approaches, is likely to benefit from further elucidation of the patterns and regulation of cytokine expression associated with MM tumors.
Am J Respir Cell Mol Biol 1995 May
PMID:The role of growth factors and cytokines in the tumorigenesis and immunobiology of malignant mesothelioma. 774 9

Gelsolin-related amyloidosis, also called familial amyloidosis, Finnish type (FAF) is an autosomal dominantly inherited disorder characterized by progressive polyneuropathy and corneal lattice dystrophy. All the analyzed patients are found to carry a nucleotide substitution of A or T for G654 in their gelsolin gene, which at the protein level results in the conversion of the 187 amino acid residue, aspartic acid, to asparagine or tyrosine, respectively. In this study, we transfected mammalian mesenchymal COS-1 cells with a derivative of the expression vector pCD-X containing cDNA coding for the wild-type (D187) and mutant forms (N187 and Y187) of plasma gelsolin. Both disease-associated mutant forms of gelsolin were found to be abnormally processed, which led to the secretion of an aberrant 68 kDa gelsolin fragment into the culture media. This fragment most probably represents a carboxy-terminal part of the protein and contains the suggested amyloid-forming sequence. Initial data were also obtained for involvement of a metalloendoprotease in the pathologic processing. This aberrant proteolysis is likely to represent a crucial initiator step in the cascade resulting in amyloid accumulation in patients' tissues.
Hum Mol Genet 1994 Dec
PMID:Toward understanding the pathogenic mechanisms in gelsolin-related amyloidosis: in vitro expression reveals an abnormal gelsolin fragment. 788 24

Alzheimer's disease is a dementing disorder affecting increasingly large numbers of individuals in the aging population. The characteristic neuropathologic changes of Alzheimer's disease are the deposition of extracellular amyloid plaques, neurons containing neurofibrillary tangles, and neuronal cell loss. The A4 amyloid peptide is the major constituent of senile plaques. In addition to the A4 peptide, senile plaques contain a variety of molecular species, including proteoglycans and inflammatory components. The presence of proteoglycans in the amyloid deposits of Alzheimer's disease and of systemic amyloidoses suggests that these molecules play an active role in the pathogenesis of amyloidosis. However, the molecular mechanisms that lead to the codeposition of amyloid peptide with proteoglycans is still unknown. Recent evidence suggests that the metabolism of proteoglycans is altered in Alzheimer's disease patients. The acute-phase response observed in the brain of patients affected by Alzheimer's disease may be responsible for this effect. In this article, we discuss the role of proteoglycans in Alzheimer's disease, and the possible interactions between factors involved in brain inflammatory mechanisms and proteoglycans in the pathogenesis of Alzheimer's disease.
Mol Neurobiol
PMID:Proteoglycans and the acute-phase response in Alzheimer's disease brain. 788 2

Amyloidosis is a generic term for a group of clinically and biochemically diverse diseases that are characterized by the deposition of an insoluble fibrillar protein in the extracellular space. Over 16 biochemically distinct amyloids are known. Despite this diversity, all amyloids have a particular ultrastructural and tinctorial appearance, a beta-pleated sheet structure, and are codeposited with a group of amyloid-associated proteins. The most common amyloidosis is Alzheimer's disease (AD), where A beta is the main component of the amyloid. Recently it has been found that A beta exists as a normal soluble protein (sA beta) in biological fluids. This links AD more closely to some of the systemic amyloidoses, where the amyloid precursor is found in the circulation normally. Numerous mutations have been found in the A beta precursor (beta PP) gene, associated with familial AD. Many mutations are also found in some of the hereditary systemic amyloidoses. For example, over 40 mutations in the transthyretin (TTR) gene are associated with amyloid. However, both A beta and TTR related amyloid deposition can occur with no mutation. The pathogenesis of amyloid is complex, and appears to be associated with genetic and environmental risk factors that can be similar in the systemic and cerebral amyloidoses.
Mol Neurobiol 1994 Feb
PMID:Unifying features of systemic and cerebral amyloidosis. 791 92

Amyloid plaques, associated with argyrophilic dystrophic neurites, and cerebral amyloid angiopathy (CAA), but no neurofibrillary tangles, were found in the brains of three middle-aged marmoset monkeys that had been injected intracerebrally (ic) 6-7 yr earlier with brain tissue from a patient with early-onset Alzheimer's disease. Such changes were not found in the brains of three age-matched control marmosets. Immunochemically the amyloid plaques and CAA stained with antibody to beta (A4)-protein. The plaques and CAA displayed dichroic birefringence when stained with Congo red and viewed under polarized light. beta (A4)-amyloid plaques and CAA were also found in the brain of one of two marmosets injected ic 6 yr previously with brain tissue from a patient with prion disease with concomitant beta (A4)-amyloid plaques and CAA. An occasional beta (A4)-amyloid plaque was found in the brains of two of four marmosets injected ic > 4.5 yr previously with brain tissue from three elderly patients, two of whom had suspected (but untransmitted) CJD. No beta (A4)-amyloid plaques or CAA were found in six marmosets who were older than the injected animals, in four marmosets that had not developed spongiform encephalopathy (SE) having been injected several years previously with human brain tissue from three younger patients with suspected or atypical prion disease, or in 10 younger marmosets who had undergone various neurosurgical procedures. Seventeen marmosets injected in the same way with brain tissue from patients or animals with SE developed SE 17-49 mo after injection. These results suggest that beta (A4)-amyloidosis is a transmissible process comparable to the transmissibility of SE.
Mol Neurobiol 1994 Feb
PMID:Induction of beta (A4)-amyloid in primates by injection of Alzheimer's disease brain homogenate. Comparison with transmission of spongiform encephalopathy. 808 26

Systemic amyloidosis of the amyloid A (AA) type, is occasionally associated with various neoplasms, but the cause is still unclear. We obtained interleukin 6 (IL-6)-producing cells designated YO from a primary culture of a malignant peritoneal mesothelioma of epithelial type obtained from a 62-year-old woman. Post mortem examination revealed that the patient had systemic amyloidosis of the AA type. The supernatant media of YO cells, as well as recombinant human IL-6, successfully induced nonneoplastic liver cells to produce serum AA (SAA). Our data suggest that IL-6 produced by the tumor cells may have played an important role in the paraneoplastic syndrome of AA amyloidosis in this patient.
Virchows Arch B Cell Pathol Incl Mol Pathol 1993
PMID:Interleukin 6-producing malignant mesothelioma. 814 57

We have isolated from a human genomic library a potentially functional and distinctive germline gene, designated IGLV6S1, that encodes for light chains of the V lambda VI subgroup. An identical germline gene was cloned from fibroblasts obtained from a patient with light-chain-associated amyloidosis (AL amyloidosis) whose serum and urine contained, respectively, a monoclonal IgG lambda VI protein and a lambda VI Bence Jones protein. Isolation and characterization of cDNA cloned from the patient's bone marrow-derived monoclonal plasma cells revealed that the nucleotide and predicted protein sequences of the rearranged gene were approximately 95% and approximately 90% homologous to those of the germline gene, respectively. The finding that the transcriptional start site for lambda VI RNA synthesis was located upstream of the putative TATA-box promoter, rather than downstream as found for the V lambda II subgroup, implies that a different transcriptional machinery controls the expression of the human V lambda VI-gene family.
Mol Immunol 1994 May
PMID:Identification and characterization of a functional human Ig V lambda VI germline gene. 819 Jan 28

The light microscopic and immunohistochemical features of a novel localized senile amyloidosis in the gastrointestinal tract of C57BL/Ka mice are described. Senile gastrointestinal amyloidosis was predominantly found in the lamina propria of the ileum, cecum and stomach and infrequently in other segments of the gastrointestinal tract. The Congo red affinity of the senile amyloid was sensitive to potassium permanganate pretreatment. The amyloid did not react with anti-AA and anti-immunoglobulin antisera, but stained positively for apoAII, a major apolipoprotein of high density lipoproteins. A similar type of amyloid, termed AApoAII, has recently been described in a systemic form of senile amyloidosis in mice. In the present study, we investigated the effect of long-term immunosuppressive treatment on the incidence of systemic AA-amyloidosis and gastrointestinal AApoAII-amyloidosis in aged C57BL/Ka mice. Gastrointestinal amyloidosis occurred in 60% of the control mice, but significantly less in mice of the immunosuppressed groups. In contrast, systemic AA-immunoreactive amyloidosis was only found in mice that were given immunosuppressive treatment. There was no codeposition of AA and AApoAII-amyloid. These findings indicate that immunosuppressive drugs have a profound effect on the incidence as well as the type of amyloidosis in C57BL/Ka mice.
Virchows Arch B Cell Pathol Incl Mol Pathol 1993
PMID:Gastrointestinal AAPOAII and systemic AA-amyloidosis in aged C57BL/Ka mice. Amyloid-type dependent effect of long-term immunosuppressive treatment. 840 15

Although both light chain amyloidosis (AL) and deposition disease (LCDD) involve the aggregation of light chain V(L) domains into highly insoluble deposits, the factors which determine both disease onset and type (amyloid fibrils (AL) or granular deposits (LCDD)) are not clear. Previously, we showed that the AL-associated replacement Arg61 --> Asn, introduced as a point mutation into the kappa V(L) domain REI, greatly destabilizes the domain and renders it susceptible to the formation of ordered, fibril-like aggregates in vitro. The importance of Arg61 for stability may be due to the role of this residue in making a key, conserved salt bridge with Asp82 located on an adjacent loop. Here we show that an Asp82 --> Ile replacement, recently identified in a V(L) associated with LCDD, also highly destabilizes REI as a point mutation and makes it susceptible to in vitro aggregate formation. The D82I aggregate, however, is dramatically different in morphology from aggregates obtained from amyloid-associated mutants, suggesting that specific amino acid residue changes can control not only the onset of aggregation disease but also aggregate morphology and disease type.
J Mol Biol 1996 Mar 22
PMID:Specificity of abnormal assembly in immunoglobulin light chain deposition disease and amyloidosis. 863 61

Serum amyloid A (SAA) is a plasma protein which has been associated with several diseases, including amyloidosis, arthritis, and atherosclerosis, and its abnormal expression, particularly in nonhepatic cells, is implicated in the pathogenesis of these diseases. Transfection and DNA-binding studies were performed to investigate the mechanism controlling cytokine-induced, nonhepatic expression of the SAA gene. We have identified a novel promoter, located between positions -280 and 224, that confers interleukin-6 (IL-6) inducibility to an SAA-chloramphenicol acetyltransferase reporter gene in both nonhepatic and hepatic cells. DNase I protection assays revealed, within this region, three homologous highly pyrimidine rich octanucleotide sequence motifs, termed SAA-activating sequences (SAS). Specific mutations within these three SAS motifs severely reduced IL-6-mediated induction of the reporter gene in transfected nonhepatic cells but not in liver cells. A nuclear factor activated by IL-6 in both hepatic and nonhepatic cells efficiently interacts with the SAS. The induction kinetics and cycloheximide sensitivity of this SAS-binding factor (SAF) suggested that de novo synthesis of this factor itself or an activator protein is essential. Loss of DNA-binding ability as a result of in vitro dephosphorylation, induction of SAA-chloramphenicol acetyltransferase reporter gene activity in the presence of genistein, a protein kinase inhibitor, further indicate that a phosphorylation step is necessary for the activation of SAF. Our results suggest that SAF is a key regulator of cytokine-mediated SAA gene expression in some nonhepatic cells.
Mol Cell Biol 1996 Apr
PMID:A novel cis-acting element is essential for cytokine-mediated transcriptional induction of the serum amyloid A gene in nonhepatic cells. 865 33


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