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PubMed1999

Med8, a subunit of the mediator CTD complex of RNA polymerase II, directly binds to regulatory elements of SUC2 and HXK2 genes.

In a search to identify new factors required for expression of SUC2 gene in Saccharomyces cerevisiae, we have partially purified a 27 kDa protein (p27) that bound both the DRSs of the HXK2 gene and the UASs of SUC2 gene. The amino terminal sequence of p27 identified the MED8 gene (open reading frame YBR193C), located in chromosome II of S. cerevisiae, as the gene coding for the protein. Disruption of this gene has demonstrated that is an essential gene for yeast growth. To determine whether the p27 protein represents the Med8 product, we expressed MED8 gene in E. coli and demonstrated that the heterologous synthesized protein specifically binds to both UASSUC2 and DRS2HXK2. This observation suggests that Med8 may be important for the coupling of the glucose repression pathway of SUC2 gene to the HXK2 gene expression. Med8 has been described as a mediator protein interacting with the CTD of the RNA polymerase II. Thus, the role of Med8 could be to act as coupling factor by linking activating and repressing transcription complexes to the RNA polymerase II holoenzyme transcriptional machinery.

Chromosome Mapping↗
PubMed2000

Vascular smooth muscle actions of carnosine as its zinc complex are mediated by histamine H(1) and H(2) receptors.

The endogenous dipeptide carnosine (beta-alanyl-L-histidine), at 0.1-10 mM, can provoke sustained contractures n rabbit saphenous vein rings with greater efficacy than noradrenaline. The effects are specific; anserine and homocarnosine are ineffective, as are carnosine's constituent amino acids histidine and beta-alanine. Zinc ions enhance the maximum carnosine-induced tension (to 127 +/- 13% of control at 10 microM Zn(total)) and muscle sensitivity is potentiated (mean K(0.5) reduced from 1.23 mM to 17 microM carnosine with 15 microM Zn(total)). The dipeptide acts as a Zn-carnosine complex (Zn. Carn). The effects of carnosine at 1 microM-10 mM (total) in the presence of 1-100 microM Zn(2+) (total) can be described as a unique function of [Zn. Carn] with an apparent K(0.5) for the complex of [7.4)(10(-8)] M. Contractures are reduced at low [Ca(2+)], unaffected by adrenoceptor antagonists, but can be blocked by antagonists to several receptor types. The most specific effect is by mepyramine, the H(1) receptor antagonist. With Zn present, carnosine can inhibit the H(1)-specific binding of [(3)H]mepyramine to isolated Guinea pig cerebella membranes. This effect of carnosine can be described as a function of the concentration of Zn. Carn with an apparent IC(50) of 2.45 microM. Like histamine, carnosine evoked an H2-mediated (cimetidine-sensitive) relaxation in the presence of mepyramine, but was less potent (10.8 +/- 3.1% of initial tension remaining at 10 mM carnosine compared with 13.4 +/- 7.5% remaining at 0.1 mM histamine). Preliminary studies with a Zn-selective fluorescent probe indicate that functionally significant levels of Zn can be released from adventitial mast cells that could modulate actions of carnosine in the extravascular space as well as those of histamine itself. We conclude that carnosine can act at the smooth muscle H(1)-receptor to provoke vasoconstriction and that it also has the potential to act at H(1)-receptors in the central nervous system. Carnosine's mode of action is virtually unique: a vascular muscle receptor apparently transduces the action of a dipeptide in the form of a metal chelate. The functional relationship of carnosine with histamine and the possible physiological relevance of Zn ions for the activity of both agents have not previously been reported.

Animals↗
PubMed2004

Requirement of Sur2 for efficient replication of mouse adenovirus type 1.

Mouse adenovirus type 1 (MAV-1) early region 1A (E1A) encodes a virulence gene in viral infection of mice. To broaden our understanding of the functions of E1A in MAV-1 pathogenesis, an unbiased experimental approach, glutathione S-transferase (GST) pulldown, was used to screen for cellular proteins that interact with E1A protein. We identified mouse Sur2, a subunit of Mediator complex, as a protein that binds to MAV-1 E1A. The interaction between Sur2 and MAV-1 E1A was confirmed in virus-infected cells. Conserved region 3 (CR3) of MAV-1 E1A was mapped as the region required for Sur2-E1A interaction, as is the case for human adenovirus E1A. Although it has been proposed that human adenovirus E1A recruits the Mediator complex to transactivate transcription of viral early genes, Sur2 function in adenovirus replication has not been directly tested previously. Studies on the functions of Sur2 with mouse embryonic fibroblasts (MEFs) showed that there was a multiplicity-dependent growth defect of MAV-1 in Sur2(-/-) MEFs compared to Sur2(+/+) MEFs. Comparison of the viral DNA and viral mRNA levels in Sur2(+/+) and Sur2(-/-) MEFs confirmed that Sur2 was important for efficient viral replication. The viral replication defects in Sur2(-/-) MEFs appeared to be due at least in part to a defect in viral early gene transcription.

ATP-Binding Cassette Transporters↗
PubMed1989

Human microvascular endothelial cells express integrin-related complexes that mediate adhesion to the extracellular matrix.

Microvascular endothelial cells (MEC) must use a set of surface receptors to adhere not only to the vascular basement membrane but, during angiogenic stimulation, to the interstitium. We examined how cultured MEC isolated from human foreskin interact with their subendothelial matrix. MEC were able to attach to diverse extracellular matrix proteins, including fibronectin (Fn), vitronectin (Vn), laminin (Ln), type I and IV collagen, as well as to fibrinogen and gelatin. Adhesion to Fn, but not to laminin or collagens, was specifically blocked in the presence of Arg-Gly-Asp (RGD)-containing peptides. When surface radioiodinated MEC were solubilized and subjected to affinity chromatography on Fn-Sepharose columns, two polypeptides of 150 and 125 kD, corresponding to the integrin heterodimer alpha 5 beta 1, were identified. MEC also express a complex of 150 (alpha) and 95 kD (beta 3) that is related to the Vn receptor. Immunofluorescent staining of MEC cultures with antibodies to the integrin beta 1 subunit demonstrated receptors on the basolateral surface at focal adhesion plaques that co-localized with vinculin and with Fn-positive matrix fibers. Occasionally, antibodies to the Vn receptor stained the vinculin-positive focal adhesion plaques that frequently co-localized with the beta 1 complex. However, in cultures of MEC that were attached to substrates coated with alternating strips of Fn and Vn, the beta 1 complex was preferentially localized to the Fn substrate, while the Vn receptor was concentrated on the Vn substrate. The results indicate that MEC express at least two different heterodimer adhesion receptors that belong to the integrin super-family and appear to have distinct ligand specificities: the Fn receptor and the Vn receptor. These receptors mediate cell adhesion to the extracellular matrix and presumably have an important role in hemostasis and neovascularization.

Binding, Competitive↗
PubMed2003

POSH acts as a scaffold for a multiprotein complex that mediates JNK activation in apoptosis.

We report that the multidomain protein POSH (plenty of SH3s) acts as a scaffold for the JNK pathway of neuronal death. This pathway consists of a sequential cascade involving activated Rac1/Cdc42, mixed-lineage kinases (MLKs), MAP kinase kinases (MKKs) 4 and 7, c-Jun N-terminal kinases (JNKs) and c-Jun, and is required for neuronal death induced by various means including nerve growth factor (NGF) deprivation. In addition to binding GTP-Rac1 as described previously, we find that POSH binds MLKs both in vivo and in vitro, and complexes with MKKs 4 and 7 and with JNKs. POSH overexpression promotes apoptotic neuronal death and this is suppressed by dominant-negative forms of MLKs, MKK4/7 and c-Jun, and by an MLK inhibitor. Moreover, a POSH antisense oligonucleotide and a POSH small interfering RNA (siRNA) suppress c-Jun phosphorylation and neuronal apoptosis induced by NGF withdrawal. Thus, POSH appears to function as a scaffold in a multiprotein complex that links activated Rac1 and downstream elements of the JNK apoptotic cascade.

Adaptor Proteins, Signal Transducing↗
PubMed1986

Difference in the in vitro metabolism of leukotrienes in the exudates from allergic and nonallergic rat pleurisies.

The metabolism of leukotrienes (LTs) in the cell-containing inflammatory exudate of rat pleurisy was studied in vitro. The exudates of both nonallergic carrageenin-induced pleurisy and IgG immune complex-mediated pleurisy converted 3H-LTB4 to 20-OH LTB4, but virtually did not metabolized 3H-LTC4 or 3H-LTE4 up to 2 hrs. 3H-LTD4 was changed to LTC4 by the exudate of non-allergic pleurisy, whereas 3H-LTD4 was metabolized to LTE4 by that of allergic pleurisy. Reflecting on the different metabolism, the gamma-glutamyl transpeptidase activity in the exudate of carrageenin-induced pleurisy was significantly higher than that in IgG immune complex mediated pleurisy. The enzyme activity was not derived from the blood itself, but from the infiltrated polymorphonuclear leukocytes. The activity of the cell homogenate in both exudates was not significantly different. Thus, it could be concluded that the difference in the metabolism of LTD4 between the nonallergic and allergic pleural exudates in vitro was mainly attributable to the enhanced activity of the gamma-glutamyl transpeptidase released in the exudate.

Animals↗
PubMed2000

Role of lipids in the progression of renal disease in systemic lupus erythematosus patients.

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease marked by immune-complex mediated lesions in small blood vessels of various organs, especially the kidneys, although other factors may also be implicated in the pathogenesis of the disease. This article focuses on the role of lipids in the progression of glomerular, vascular and tubulo-interstitial lesions in two patients with lupus nephritis associated with pronounced hyper- and dyslipidemia. The pathogenesis of progressive glomerulosclerosis in both patients appears to be multifactorial. In addition to immune complex mediated lupus glomerulonephritis, progressively active in the first patient, severe nephrotic-range persistent proteinuria, arterial hypertension associated with hyperfiltration and hyperperfusion injuries and, to a minor extent, hyper- and dyslipidemia were observed. Immunological and non-immunological factors were shown to contribute to the development of tubulo-interstitial lesions. In both patients, in addition to local immune deposits, prominent tubulo-interstitial lipid deposits were probably causally related to both hyperlipidemia and the increased permeability of the glomerular filtration barrier. Tubular lesions were highlighted by intracytoplasmic lipid droplets as well as small cleft-like spaces found to be impacted in the tubular lumina. They were seen to penetrate tubular epithelial cells and eventually lodge in the interstitium, surrounded by mononuclear cell infiltrates and foam cells. In both patients, hypertensive angiopathy and extraglomerular vascular immune deposits were demonstrated. In addition, in the second patient, arteriolar and small arterial hyaline was found at the age of 28 years to be full of lipids and calcium precipitates, suggesting a peripheral atherosclerosis-like process which never occurs as a natural age-related condition. In conclusion, all parts of the nephron may be involved in the pathogenetic process causally related or influenced by hyper- or dyslipidemia. Associated either with endothelial cell injury and consequent insudation of lipids in the vascular walls, glomerular filtration barrier injury with hyperfiltration, or tubulo-interstitial lipid deposition, the mechanism of tissue damage by lipids in all parts of the nephron shares similarities with the pathogenesis of systemic atherosclerosis.

Adult↗
PubMed1999

Dissection of a surface-exposed portion of the cAMP-CRP complex that mediates transcription activation and repression.

The Escherichia coli cAMP receptor protein (CRP) is essential for the activation and repression of transcription initiation at promoters in the CytR regulon. CRP performs these activities by making direct protein-protein interactions to the alpha-subunits of RNA polymerase and to the CytR regulator. Strikingly, it has been shown that amino acids of CRP that are critical for communication with the two partner proteins are located in close proximity on the surface of CRP. Here, we have dissected this surface in order to pinpoint the 'repression region' of CRP and to assess whether it overlaps with the characterized 'activating region'. Our results established that residues 12, 13, 17, 105, 108 and 110 are essential for the interaction with CytR and confirmed that 'activating region' 2 of CRP is made up of residues 19, 21 and 101. In the crystallographic structure of the CRP-DNA complex, the two sets of determinants are located immediately adjacent to each other forming a consecutive surface-exposed patch. The 'repression region' is chemically complementary to the characterized region on CytR that is essential for protein-protein communication to CRP. Moreover, the results provide insight into the mechanism by which CytR might prevent CRP-mediated transcription.

Alanine↗
PubMed1993

cis-acting sequences in the Aleutian mink disease parvovirus late promoter important for transcription: comparison to the canine parvovirus and minute virus of mice.

We are currently investigating the regulation of transcription of the Aleutian mink disease parvovirus (ADV). ADV causes a chronic immune complex-mediated condition known as classical Aleutian disease, characterized by slow viral replication. This slow replication is an intrinsic property of ADV and distinguishes it from the more prototypic parvoviruses such as minute virus of mice (MVM) and canine parvovirus (CPV). We have previously suggested a role for the weak ADV promoters in the slow replication and thereby the absence of acute cytopathology and instead establishment of persistent ADV infection with progressive immune complex-mediated chronic lesions. In this study, we have mapped the cis-acting sequences around the ADV P36 promoter responsible for both constitutive transcription and transactivation mediated by the nonstructural protein 1. The mapping was performed by using endpoint deletions of the ADV P36 promoter and by making chimeras between the ADV P36 and MVM P38 promoters. We found the weak constitutive activity of the ADV P36 promoter to be caused by suboptimal promoter proximal sequences, while the low level of transactivation was caused mainly by an upstream region including sequences with homology to the transactivation responsive element (tar) of the H-1 parvovirus (M.-L. Gu, F.-X. Chen, and S. L. Rhode, Virology 187:10-17, 1992). We also found the corresponding regions in the MVM and CPV P38 promoters to be important for transactivation of these promoters by making 5' deletions of the promoter region. In addition, it was found that MVM tar-like and upstream sequences could transfer high nonstructural protein 1 responsiveness to the ADV promoter even though the distance between the tar-like element and the TATA box was significantly changed. On the basis of comparative data for ADV, MVM, CPV, and H-1, a new clustered motif (TTGGTT) is proposed to be the responsive cis-acting element for transactivation. Homology comparison of the specific transcriptional elements of the ADV P36, MVM P38, and CPV P38 promoters suggests that few, but crucial, changes in the ADV P36 promoter and upstream region are responsible for the weak constitutive activity and low level of transactivation of the ADV P36 promoter.

Aleutian Mink Disease↗
PubMed1998

Neurite fasciculation mediated by complexes of axonin-1 and Ng cell adhesion molecule.

Neural cell adhesion molecules composed of immunoglobulin and fibronectin type III-like domains have been implicated in cell adhesion, neurite outgrowth, and fasciculation. Axonin-1 and Ng cell adhesion molecule (NgCAM), two molecules with predominantly axonal expression exhibit homophilic interactions across the extracellular space (axonin- 1/axonin-1 and NgCAM/NgCAM) and a heterophilic interaction (axonin-1-NgCAM) that occurs exclusively in the plane of the same membrane (cis-interaction). Using domain deletion mutants we localized the NgCAM homophilic binding in the Ig domains 1-4 whereas heterophilic binding to axonin-1 was localized in the Ig domains 2-4 and the third FnIII domain. The NgCAM-NgCAM interaction could be established simultaneously with the axonin-1-NgCAM interaction. In contrast, the axonin-1-NgCAM interaction excluded axonin-1/axonin-1 binding. These results and the examination of the coclustering of axonin-1 and NgCAM at cell contacts, suggest that intercellular contact is mediated by a symmetric axonin-12/NgCAM2 tetramer, in which homophilic NgCAM binding across the extracellular space occurs simultaneously with a cis-heterophilic interaction of axonin-1 and NgCAM. The enhanced neurite fasciculation after overexpression of NgCAM by adenoviral vectors indicates that NgCAM is the limiting component for the formation of the axonin-12/NgCAM2 complexes and, thus, neurite fasciculation in DRG neurons.

Animals↗
PubMed2003

Mouse ribonucleotide reductase R2 protein: a new target for anaphase-promoting complex-Cdh1-mediated proteolysis.

Ribonucleotide reductase consists of two nonidentical proteins, R1 and R2, and catalyzes the rate-limiting step in DNA precursor synthesis: the reduction of ribonucleotides to deoxyribonucleotides. A strictly balanced supply of deoxyribonucleotides is essential for both accurate DNA replication and repair. Therefore, ribonucleotide reductase activity is under exquisite control both transcriptionally and posttranscriptionally. In proliferating mammalian cells, enzyme activity is regulated by control of R2 protein stability. This control, which responds to DNA damage, is effective until cells pass into mitosis. We demonstrate that the mitotic degradation and hence the overall periodicity of R2 protein levels depends on a KEN box sequence, recognized by the Cdh1-anaphase-promoting complex. The mouse R2 protein specifically binds Cdh1 and is polyubiquitinated in an in vitro ubiquitin assay system. Mutating the KEN signal stabilizes the R2 protein during mitosisG(1) in R2 protein-overexpressing cells. The degradation process, which blocks deoxyribonucleotide production during G(1), may be an important mechanism protecting the cell against unscheduled DNA synthesis. The newly discovered p53-induced p53R2 protein that lacks a KEN box may supply deoxyribonucleotides for DNA repair during G(0)G(1).

3T3 Cells↗
PubMed2003

AKT-independent protection of prostate cancer cells from apoptosis mediated through complex formation between the androgen receptor and FKHR.

Recent studies suggested that the protection of cell apoptosis by AKT involves phosphorylation and inhibition of FKHR and related FOXO forkhead transcription factors and that androgens provide an AKT-independent cell survival signal in prostate cancer cells. Here, we report receptor-dependent repression of FKHR function by androgens in prostate cancer cells. Transcriptional analysis demonstrated that activation of the androgen receptor caused an inhibition of both wild-type FKHR and a mutant in which all three known AKT sites were mutated to alanines, showing that the repression is AKT independent. In vivo and in vitro coprecipitation studies demonstrated that the repression is mediated through protein-protein interaction between FKHR and the androgen receptor. Mapping analysis localized the interacting domains to the carboxyl terminus between amino acids 350 and 655 of FKHR and to the amino-terminal A/B region and the ligand binding domain of the receptor. Further analysis demonstrated that the activated androgen receptor blocked FKHR's DNA binding activity and impaired its ability to induce Fas ligand expression and prostate cancer cell apoptosis and cell cycle arrest. These studies identify a new mechanism for androgen-mediated prostate cancer cell survival that appears to be independent of the activity of the receptor on androgen response element-mediated transcription and establish FKHR and related FOXO forkhead proteins as important nuclear targets for both AKT-dependent and -independent survival signals in prostate cancer cells.

Apoptosis↗
PubMed1994

[Immune complex and vasculitis].

In the early 1900s, von Pirquet first introduced the concept that antigen antibody complexes might cause disease. Since that time, systemic necrotizing vasculitis is believed to be a typical form of immune complex-mediated vasculitis and it may be found in many disorders associated with immunological abnormalities. In 1866, Kusmaul and Maier reported a case with multilesions of necrotizing vasculitis named as periarteritis nodosa which is now nominated as polyarteritis nodosa characterized by the presence of focal inflammatory lesions in small and medium-sized arteries. Besides polyarteritis nodosa, necrotizing vasculitis is frequently found in connective tissue diseases, especially in SLE and RA. Granulomatous vasculitis is a definitely different type of vasculitis from necrotizing vasculitis and known to be found in Wegener's granulomatosis. Whether or not granulomatous vasculitis is an immune complex-mediated disease is unknown, but it can be produced experimentally in several settings. In a experimental model of serum sickness, animals who are hyperimmune responders have widespread granulomatous lesions similar to Wegener's granulomatosis in histology. Intravenous injection of complete Freund's adjuvant in rabbits followed by intravenous administration of human IgM rheumatoid factor is capable of inducing a marked pulmonary granulomatous reaction. The relation of these observations to human Wegener's granulomatosis is uncertain, but the histology and location of the lesions are strikingly similar to human disease. Vasculitis involved in large and medium-sized arteries is seen in two different types of diseases known as temporal arteritis and Takayasu's arteritis. Circulating and tissue-bound immune complexes have been found in both conditions. Most common vasculitis in childhood is Schonlein-Henoch purpura in North America and Kawasaki disease in Japan.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigen-Antibody Complex↗
PubMed2000

Therapeutic inhibition of the complement system. Y2K update.

Activation of complement is an essential part of the mechanism of pathogenesis of a large number of human diseases; its inhibition by pharmacological means is likely to suppress disease processes in complement mediated diseases. From this point of view low molecular weight synthetic inhibitors of complement are being developed and high molecular weight natural inhibitors of human origin present in plasma or embedded in cell membrane are being purified or produced in their recombinant forms. This review is concerned with high molecular weight inhibitors, some of which are already in clinical use but may be efficacious in many other diseases in which they have not yet been tried. C1-esterase inhibitor (C1-INH) concentrate prepared from human plasma is being successfully used for the treatment of hereditary angioneurotic edema. Recently, C1-INH has been found to be consumed in severe inflammation and has been shown to exert beneficial effects in several inflammatory conditions such as human sepsis, post-operative myocardial dysfunction due to reperfusion injury, severe capillary leakage syndrome after bone marrow transplantation, reperfusion injury after lung transplantation, burn, and cytotoxicity caused by IL-2 therapy in cancer. Factor I has been used for the treatment of factor I deficiency. Recombinant soluble forms of membrane cofactor protein (MCP), and decay accelerating factor (DAF) have not yet been tried in humans but have been shown to be effective in immune complex mediate inflammation in animals. Organs of pigs transgenic for one or more of human membrane regulators of complement namely membrane cofactor protein (MCP), decay accelerating factor (DAF) or CD59, are being produced for transplantation into humans. They have been shown to be resistant to hyperacute rejection in non-human primates; acute vascular rejection is still a problem in their clinical use. It is hoped that these observations together with future developments will make xeno-transplantation in clinical practice a reality. Several recombinant variants of complement receptor 1 (CR1) have been produced. The most effective of these appears to be sCR1-SLe x, sCR1 part of which inhibits complement and carbohydrate Sle x moiety inhibits selectin mediated interactions of neutrophils and lymphocytes with endothelium. Although clinical trials of sCR1 in humans is eagerly awaited, several of the recombinant versions of sCR1 have been shown to suppress ischemia/reperfusion injury, thermal trauma, and immune complex mediated inflammation. They have also been shown to be effective in experimental models of systemic sclerosis, arthritis, myasthenia gravis, Guillain Barré syndrome and glomerulonephritis. Intravenous immunoglobulin, three of the most prominent properties of which are neutralization of autoantibody activity, suppression of autoantibody production and inhibition of complement activity, is being used in several diseases. These include autoimmune thrombocyopenic purpura, Kawasaki disease and several neurological diseases such as myasthenia gravis and Guillain Barre syndrome. In many uncontrolled small scale studies intravenous immunoglobulin has been shown to be effective in many immunological including dermatological diseases; controlled clinical trials in a large number of patients with these diseases is needed to establish the efficacy. It is hoped that in future therapeutic inhibition of complement will be one of the major approaches to combat many human diseases.

Animals↗
PubMed1995

Pattern of glomerular involvement in human immunodeficiency virus-infected patients: an Italian study.

Renal biopsy specimens from 26 adult human immunodeficiency virus (HIV)-infected patients with glomerular involvement were reviewed from the files of three hospital pathology services in Northern Italy. All the patients were Italian and most (19 of 26 patients) were intravenous drug addicts. The types of glomerular lesions were as follows: minimal-change glomerulopathy (two cases), mesangial proliferative glomerulonephritis (GN) with scanty immunoglobulin deposits (four cases), and various patterns of immune complex-mediated glomerulonephritis, including postinfectious GN (six cases), membranoproliferative GN (one case), membranous GN (three cases), immunoglobulin (Ig) A nephropathy (four cases), a mixed membranous and proliferative (three cases) and diffuse proliferative lupus-like pattern with subendothelial deposits, and intraluminal thrombi (two cases) or subepithelial and subendothelial deposits (one case). None of the patients had evidence of HIV-associated nephropathy. Our study confirms previous observations on the low incidence of HIV-associated nephropathy among white HIV-infected patients in Europe, where immune complex-mediated GN seems to predominate. Apart from the frequent electron microscopic observation of endothelial tubuloreticular structures, none of the reported lesions could be distinguished on morphologic grounds from those occurring in uninfected patients. The high variability of the glomerular lesions upholds the need for accurate diagnosis for the clinician confronted with an HIV-positive patient with suspected glomerular involvement.

Adult↗
PubMed2005

Kissing complex RNAs mediate interaction between the Fragile-X mental retardation protein KH2 domain and brain polyribosomes.

Fragile-X mental retardation is caused by loss of function of a single gene encoding the Fragile-X mental retardation protein, FMRP, an RNA-binding protein that harbors two KH-type and one RGG-type RNA-binding domains. Previous studies identified intramolecular G-quartet RNAs as high-affinity targets for the RGG box, but the relationship of RNA binding to FMRP function and mental retardation remains unclear. One severely affected patient harbors a missense mutation (I304N) within the second KH domain (KH2), and some evidence suggests this domain may be involved in the proposed role of FMRP in translational regulation. We now identify the RNA target for the KH2 domain as a sequence-specific element within a complex tertiary structure termed the FMRP kissing complex. We demonstrate that the association of FMRP with brain polyribosomes is abrogated by competition with the FMRP kissing complex RNA, but not by high-affinity G-quartet RNAs. We conclude that mental retardation associated with the I304N mutation, and likely the Fragile-X syndrome more generally, may relate to a crucial role for RNAs harboring the kissing complex motif as targets for FMRP translational regulation.

Amino Acid Motifs↗
PubMed1989

Systemic lupus erythematosus of the central nervous system: 2. Molecular theories and models for mental disease.

A molecular theory attempting to account for the complexity and diversity of the manifestations of systemic lupus erythematosus (SLE) central nervous system (CNS) disease is presented. The clinical manifestations of seizures, pareses, and movement and cranial nerve disorders can be accounted for primarily by immune-complex-mediated small and medium-sized cerebral vasculopathy. The disorders of thought and affect can be explained predominantly by systemic and intrathecal synthesis of antineuronal autoantibodies and brain-enzyme-inhibiting factors leading to alterations in the quantity of mesolimbic neurotransmitter release. It is possible that a multitude of different molecular pathologic derangements can lead to the same or different CNS dysfunctions. The final clinical expression of CNS disease in patients with SLE is dictated by the permutations and combinations of the individuals' underlying genetic predisposition, environmental triggers, specific systemic and intrathecal antineuronal autoantibodies, and the diversity and extent of immune-complex-mediated cerebral vasculopathy. Ways in which SLE-CNS disease may be viewed as a theoretical model for the nature and etiology of mental disease are discussed.

Autoantibodies↗
PubMed2004

Necrotizing glomerulonephritis caused by Bartonella henselae endocarditis.

Glomerulonephritis secondary to endocarditis is uncommon and usually associated with valvular infection by blood culture-positive bacteria. We report 3 cases of necrotizing glomerulonephritis associated with culture-negative endocarditis caused by Bartonella henselae. Two of the patients presented with renal abnormalities and were investigated for endocarditis after results of renal biopsy. All 3 patients had an immune complex-mediated necrotizing and crescentic glomerulonephritis with mesangial and capillary wall deposition of immunoglobulin M (IgM), IgG, and C3. Electron microscopy showed immune-type electron-dense deposits in the mesangium and segmental subendothelial (2 cases) or subepithelial (1 case) deposits. Patients were treated with antibiotics, including azithromycin or doxycycline and ceftriaxone or tobramycin. In addition, 2 patients were administered steroids and 2 patients underwent valve replacement surgery. The 2 patients who underwent cardiac surgery were discharged from the hospital with stable renal function. The third patient died 4 months after hospital admission of renal failure. In conclusion, glomerulonephritis caused by B henselae endocarditis is an immune complex-mediated disease characterized by segmental necrotizing and crescentic glomerular lesions that can respond to aggressive medical and surgical therapy.

Adult↗