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)

SAF-1, a zinc finger transcription factor, is activated by a number of inflammatory agents, including interleukin-1 (IL-1) and IL-6. It is involved in the cytokine-mediated transcriptional induction of serum amyloid A, an acute-phase plasma protein that is associated with the pathogenesis of reactive amyloidosis, rheumatoid arthritis, and atherosclerosis. Here, we show that the mitogen-activated protein (MAP) kinase signaling pathway regulates cytokine-mediated induction of the DNA-binding activity and transactivation potential of SAF-1. Phosphorylation of endogenous SAF-1 in response to IL-1 and IL-6 was markedly inhibited by the addition of MAP kinase inhibitors. Consistent with this finding, we show that a consensus MAP kinase phosphorylation site, PPTP, within SAF-1 could be phosphorylated by MAP kinase in vitro. To analyze the contribution of MAP kinase in the activation of SAF-1, we prepared two independent mutant proteins in which the threonine residue of the PPTP motif was altered to either valine or alanine. These mutant proteins lost the ability to be phosphorylated by MAP kinase both in vivo and in vitro and exhibited a significantly reduced ability to promote expression of the SAF-1-regulated promoter. While the DNA-binding activity of wild-type SAF-1 protein was markedly increased upon phosphorylation with MAP kinase, no such increase could be detected with the mutant SAF-1 proteins. Further analysis with the GAL-4 reporter system showed that mutation of the MAP kinase phosphorylation site considerably lowers the transactivation potential of SAF-1. Together, these results show that activation of SAF-1 in response to IL-1 and -6 is mediated via MAP kinase-regulated phosphorylation.
Mol Cell Biol 2002 Feb
PMID:Cytokine-responsive induction of SAF-1 activity is mediated by a mitogen-activated protein kinase signaling pathway. 1180 95

Familial amyloidotic polyneuropathy (FAP) caused by amyloidogenic transthyretin (ATTR) mutations is the most common form of hereditary amyloidosis. We investigated the diagnostic value of the bone scanning agent technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) in this disease. Eight patients (four males, four females; age 54.4+/-8.3 years, range 43-67 years) with ATTR-FAP proven by immunohistochemistry and molecular analysis and a control group comprising ten oncological out-patients (five males, five females; age 53.4+/-8.5 years, range 34-66 years) without evidence of bony metastases were studied using 99mTc-DPD. Whole body tracer retention was 80.1%+/-10.3% (range 65.1%-94.8%) in FAP patients and 55.7%+/-8.1% (range 40.2%-66.7%) in controls at 3 h p.i. (P<0.001), and cardiac uptake was 7.3%+/-2.2% (range 4.2%-10.1%) in FAP patients and 3.1%+/-0.5% (range 2.3%-4.0%) in controls (P<0.001). The heart/whole body uptake ratio was 8.9%+/-1.7% (range 6.5%-11.0%) in FAP patients and 5.6%+/-0.5% (range 5.1%-6.8%) in controls (P<0.001). The three FAP patients with the highest cardiac tracer uptake had cardiomyopathy or arrhythmia. 99mTc-DPD scintigraphy is proposed as a simple and valuable diagnostic aid to evaluate the severity of the disease and the risk of concomitant heart problems.
Eur J Nucl Med Mol Imaging 2002 Mar
PMID:99mTc-DPD scintigraphy in transthyretin-related familial amyloidotic polyneuropathy. 1200 14

Disease-modifying therapies are being developed for Alzheimer's disease (AD). These are expected to slow the clinical progression of the disease or delay its onset. Cerebral accumulation of amyloid beta (A beta) peptides is an early and perhaps necessary event for establishing AD pathology. Consequently therapies aimed at attenuating brain amyloidosis are expected to be disease modifying. Based on the epidemiological evidence pointing to a link between cholesterol metabolism and AD and the numerous laboratory studies implicating cholesterol in the process of A beta production and accumulation, it is now believed that cholesterol-lowering therapies will be of value as disease modifying agents. Several epidemiological studies revealed that statin use for the treatment of coronary arterial disease is associated with a decreased prevalence or a decreased risk of developing AD. These observations require both preclinical and clinical validation. The former involves testing statins in one or more animal models of AD in order to establish which disease features are affected by statin treatment, the relative efficacy with which different statins modify these features and the mechanism(s) by which statins affect AD phenotypes. The latter requires prospective, randomized, placebo controlled trials to evaluate the effect of statin treatment on cognitive and AD biomarker outcomes. We have initiated a study aimed at determining the effects of atorvastatin (Lipitor), a statin with the largest US market share, on brain A beta deposition in the PSAPP transgenic mouse model of Alzheimer's amyloidosis. Our results indicate that Lipitor treatment markedly attenuates A beta deposition in this animal model.
J Mol Neurosci
PMID:Statin therapy for Alzheimer's disease: will it work? 1221 73

To date, transmissibility of amyloid diseases has not been thoroughly investigated. Although only some of these conformational disorders are considered infectious, all amyloid diseases could be infectious under certain conditions. For transmissibility, endogenous expression of an amyloidogenic peptide required, as well as the presence of an inoculum that is rich in amyloid fibrils and/or their precursors. Notably, administration of one type of amyloid might result in deposition of a different amyloid. Various cofactors could be essential for transmission - some might chaperone the amyloid peptides and/or fibrils, thereby directly facilitating their propagation; others might indirectly stabilize and/or increase levels of conformers with a high beta-sheet content. It is possible that these chaperones are induced by inflammation, which itself can lead to secondary amyloidosis. Thus, amyloid-related therapeutic approaches should not be based on administration of amyloidogenic peptides in conjunction with an inflammatory stimulus, such as in a recently halted clinical trial for Alzheimer's disease.
Trends Mol Med 2002 Sep
PMID:Infectivity of amyloid diseases. 1222 7

It is known that hen egg white lysozyme (HEWL) forms amyloid fibrils. Since HEWL is one of the proteins that have been studied most extensively and is closely related to human lysozyme, the variants of which form the amyloid fibrils that are related to hereditary systemic amyloidosis, this protein is an ideal model to study the mechanism of amyloid fibril formation. In order to gain an insight into the mechanism of amyloid fibril formation, systematic and detailed studies to detect and characterize various structural states of HEWL were conducted. Since HEWL forms amyloid fibrils in highly concentrated ethanol solutions, solutions of various concentrations of HEWL in various concentrations of ethanol were prepared, and the structures of HEWL in these solutions were investigated by small-angle X-ray and neutron scattering. It was shown that the structural states of HEWL were distinguished as the monomer state, the state of the dimer formation, the state of the protofilament formation, the protofilament state, and the state towards the formation of amyloid fibrils. A phase diagram of these structural states was obtained as a function of protein, water and ethanol concentrations. It was found that under the monomer state the structural changes of HEWL were not gross changes in shape but local conformational changes, and the dimers, formed by the association at the end of the long axis of HEWL, had an elongated shape. Circular dichroism measurements showed that the large changes in the secondary structures of HEWL occurred during dimer formation. The protofilaments were formed by stacking of the dimers with their long axis (nearly) perpendicular to and rotated around the protofilament axis to form a helical structure. These protofilaments were characterized by their radius of gyration of the cross-section of 2.4nm and the mass per unit length of 16,000(+/-2300)Da/nm. It was shown that the changes of the structural states towards the amyloid fibril formation occurred via lateral association of the protofilaments. A pathway of the amyloid fibril formation of HEWL was proposed from these results.
J Mol Biol 2002 Oct 18
PMID:An Insight into the pathway of the amyloid fibril formation of hen egg white lysozyme obtained from a small-angle X-ray and neutron scattering study. 1238 18

Type 2 diabetes mellitus (DM2) is characterized metabolically by defects in both insulin secretion and insulin action, resulting in hyperglycemia. Histopathologically, DM2 is characterized by depositions of protein in the pancreatic islets. This 'islet amyloid' is present in >90% of patients with DM2, as well as in monkeys and cats with DM2. The pathogenesis of DM2 is heterogeneous and multifactorial, although insulin resistance seems to be the predominant initiating factor for development of the disease. In the longer term, an insulin secretion defect is also revealed (referred to as 'beta-cell failure'), resulting in clinically manifest diabetes. Recent data, particularly from transgenic mouse studies, indicate that islet amyloidosis is a diabetogenic factor, which is both consequence (of insulin resistance) and cause (of beta-cell failure) of DM2. Available transgenic mouse models with islet amyloid formation in vivo will provide the opportunity to assess the effectiveness of novel anti-amyloidogenic therapies, for which promising results are emerging.
Mol Cell Endocrinol 2002 Nov 29
PMID:Role of islet amyloid in type 2 diabetes mellitus: consequence or cause? 1243 14

The common form of spontaneous diabetes mellitus that occurs in domestic cats bears close resemblance clinically and pathologically to human type 2 diabetes mellitus (T2DM). For example, the typical diabetic cat is obese and middle-aged, and has low but detectable circulating insulin levels. However, the most striking similarity is the occurrence of islet amyloidosis (IA) in nearly all diabetic cats and in over 90% of humans with T2DM. IA in both humans and cats is derived from islet amyloid polypeptide (IAPP, or amylin) which is a hormone produced and secreted along with insulin by the pancreatic beta cells. Since all cats and humans normally produce IAPP, additional factors must be invoked in order to explain the development of IA. Several lines of evidence support the concept that IA is caused by chronically increased stimulus for beta cells to secrete IAPP (and insulin). For example, peripheral insulin resistance such as in chronic obesity results in increased IAPP and insulin secretion. A recent study, in which diabetes mellitus was induced in cats, demonstrated that IAPP hypersecretion was induced by treatment with a sulfonylurea drug and resulted in 4/4 cats in this group developing IA. In contrast, cats treated with insulin had low IAPP secretion and minimal IA developed in 1/4 cats. Several human-IAPP transgenic mouse models, in which there is IAPP overexpression, also support the notion that prolonged high expression of IAPP leads to IA. In vitro models of IAPP overexpression also support this mechanism for IA formation and by demonstrating an association between IA formation and beta cell toxicity, suggest a linkage between IA formation and loss of beta cells in T2DM. A recent study has indicated that intermediate-sized IAPP-derived amyloid fibrils can disrupt cell membranes and therefore, may be involved in the destruction of beta cells. Striking parallels between the pathogenesis of IA and beta-amyloid plaque formation in Alzheimer's disease suggest possible parallel pathogenetic mechanisms of cell death and provide potential avenues for future studies into the pathogenesis of IA.
Mol Cell Endocrinol 2002 Nov 29
PMID:Pathogenesis of feline diabetes mellitus. 1243 15

APC-80200 (Mylovenge) has been developed for the treatment of B-cell malignancies and is currently in phase II clinical trials as a therapeutic vaccine for patients with advanced multiple myeloma. This vaccine candidate appears to be of particular benefit in patients who have received high-dose chemotherapy to reduce tumor load following stem cell rescue. APC-80200 is also being tested in patients with amyloidosis.
Curr Opin Mol Ther 2002 Oct
PMID:Technology evaluation: APC-80200, Dendreon. 1243 55

The lambda-type light chain dimer from a patient (Mcg) with multiple myeloma and amyloidosis was a pioneer protein for determining the three-dimensional structures of immunoglobulins, understanding the effects of ligand binding, and exploring the use of combinatorial methods to identify novel peptides complementary to protein active sites. Despite 30 years of intense study, there are still unanswered questions about the structure of the Mcg dimer, especially with respect to positions of hydrogen atoms and solvent molecules. In the present report, we describe two techniques that will help define the roles of solvent in ligand interactions and complex formation with this immunoglobulin fragment: (1) introduction of helium as a cryogenic agent during X-ray data collection; and (2) addition of neutron diffraction analyses. These techniques should provide improved resolution, and a more accurate structure of the Mcg dimer. Resolution enhancements of 0.5 A have been achieved in preliminary experiments with cryogenic helium, as compared with the best X-ray diffraction data obtained previously. In the near future, neutron diffraction studies should produce the first hydrogen structure for the Mcg dimer and help elucidate the ligand preferences and amyloidogenic properties of this eminently useful protein.
J Mol Recognit
PMID:Mcg in 2030: new techniques for atomic position determination of immune complexes. 1244 7

Significant breakthroughs in our understanding of the molecular basis of the inflammatory response have been achieved in the past five years, with the successive identification of the genetic basis of all known hereditary periodic-fever syndromes. Impaired cytokine recognition and defective signalling molecules have been implicated in the inception of recurrent attacks of fever with acute-phase protein response. Disorders of interleukin-1 processing and of regulation of nuclear factor kappaB transcription factor, and possibly defective apoptosis, might be involved in the pathogenesis of all but one of these disorders. Mutations in genes of both the pyrin and tumour-necrosis-factor-receptor superfamilies are postulated to lead to the survival of leukocytes that would ordinarily undergo apoptosis, and ultimately to a prolonged inflammatory response. Improved therapies have reduced the incidence of systemic amyloidosis, but this complication remains the most frequent cause of death.
Trends Mol Med 2002 Dec
PMID:Genetic clues to understanding periodic fevers, and possible therapies. 1247 Sep 87


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