Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Suppressor of cytokine signalling (SOCS) proteins act as part of a classical negative feedback loop regulating cytokine signal transduction. Expression of SOCS proteins is induced in response to cytokines and down-regulates the cytokine signal by inhibiting the JAK/STAT pathway. Growth hormone (GH) was previously shown to induce strong transient expression of SOCS-3 and to a lesser extent CIS, SOCS-1 and SOCS-2 in mouse liver (Adams, T.E., Hansen, J.A., Starr, R., Nicola, N.A., Hilton, D.J., Billestrup, N., 1998. Growth hormone preferentially induces the rapid, transient expression of SOCS-3, a novel inhibitor of cytokine receptor signalling. J. Biol. Chem. 273, 1285-1287.). In this work we have compared GH-induced SOCS gene expression in wild-type and STAT5b-deficient mice, and show that STAT5b is required for the induction of SOCS-2 and SOCS-3 in liver. In contrast, the absence of STAT5b has no effect on the GH-induced expression of CIS and SOCS-2 mRNA in the mammary gland. Suprisingly, there is no activation of SOCS-3 expression in mammary glands of wild-type and STAT5b mutant mice following GH administration. These results highlight both tissue- and factor-specific differences in the regulation of SOCS gene expression by STAT5a/b.
Mol Cell Endocrinol 1999 Dec 20
PMID:STAT5b mediates the GH-induced expression of SOCS-2 and SOCS-3 mRNA in the liver. 1063 Apr 11

Mycobacterium tuberculosis and Mycobacterium leprae are the ethiological agents of tuberculosis and leprosy, respectively. After performing extensive comparisons between genes from these two GC-rich bacterial species, we were able to construct a set of 275 homologous genes. Since these two bacterial species also have a very low growth rate, translational selection could not be so determinant in their codon preferences as it is in other fast-growing bacteria. Indeed, principal-components analysis of codon usage from this set of homologous genes revealed that the codon choices in M. tuberculosis and M. leprae are correlated not only with compositional constraints and translational selection, but also with the degree of amino acid conservation and the hydrophobicity of the encoded proteins. Finally, significant correlations were found between GC3 and synonymous distances as well as between synonymous and nonsynonymous distances.
J Mol Evol 2000 Jan
PMID:Gene expression, amino acid conservation, and hydrophobicity are the main factors shaping codon preferences in Mycobacterium tuberculosis and Mycobacterium leprae. 1065 59

Previous in vitro studies in rat microsomal preparations suggested that thalidomide is metabolized by the cytochrome P450 system (CYP). In this study, we examined the extent of thalidomide metabolism by preparations of pooled human microsomes, microsomes containing cloned human CYP isozymes (CYPIA2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4), and Hansen's disease patients. Results indicated that thalidomide was a poor substrate for CYP isozymes. Alteration of incubation buffer, pH, incubation time, and microsome and thalidomide concentrations did not increase the production of any metabolites. Thalidomide also did not inhibit metabolism of CYP-specific substrates and therefore any interactions with other drugs that are metabolized by the same enzyme system are unlikely. Hansen's patients were given a single oral dose of thalidomide (400 mg), and their blood and urine were collected at time points up to 72 hours, processed, and analyzed by tandem mass spectrometry. Although thalidomide was present in the plasma and urine, no metabolites were found in the plasma and very low amounts of the 5-OH thalidomide metabolite were present in the urine. These results suggest that thalidomide does not undergo significant metabolism by human CYP and that clinically important interactions between thalidomide and drugs that are also metabolized by this enzyme system are unlikely. The major route of thalidomide breakdown in humans and animals is through spontaneous hydrolysis with subsequent elimination in the urine.
J Biochem Mol Toxicol 2000
PMID:Metabolism of thalidomide in human microsomes, cloned human cytochrome P-450 isozymes, and Hansen's disease patients. 1071 29

We examined details of the fast linear prediction (FLP) analysis of time domain data. The FLP method is introduced by Gesmar and Hansen [J. Magn. Reson., Ser. A 106 (1994) 236] to improve computational efficiency of the LP analysis. We focused on two characteristic features of FLP inherited from the lattice algorithm. The first is bi-directional prediction. One can obtain both forward and backward prediction models by single execution of FLP. It is found that distances between the forward and backward prediction roots in a complex plane can be used to determine a number of resonance lines. We showed that the method utilizing the distance is as effective as that using the singular value of the singular value decomposition (SVD) analysis. Secondly, the FLP method gives prediction models for all of smaller prediction orders than some given value. This character enables one to examine a prediction order dependence of spectral parameters estimated by the analysis. We found that there were significant differences in the order dependence of the estimated frequencies between true and false resonance signals.
Spectrochim Acta A Mol Biomol Spectrosc 2000 Feb 01
PMID:Utilization of characteristics of fast linear prediction based on the lattice algorithm in an analysis of time domain magnetic resonance. 1072 42

Despite over a century of research, tuberculosis remains a leading cause of infectious death worldwide. Faced with increasing rates of drug resistance, the identification of genes that are required for the growth of this organism should provide new targets for the design of antimycobacterial agents. Here, we describe the use of transposon site hybridization (TraSH) to comprehensively identify the genes required by the causative agent, Mycobacterium tuberculosis, for optimal growth. These genes include those that can be assigned to essential pathways as well as many of unknown function. The genes important for the growth of M. tuberculosis are largely conserved in the degenerate genome of the leprosy bacillus, Mycobacterium leprae, indicating that non-essential functions have been selectively lost since this bacterium diverged from other mycobacteria. In contrast, a surprisingly high proportion of these genes lack identifiable orthologues in other bacteria, suggesting that the minimal gene set required for survival varies greatly between organisms with different evolutionary histories.
Mol Microbiol 2003 Apr
PMID:Genes required for mycobacterial growth defined by high density mutagenesis. 1265 46

The recently described family of Toll-like receptors (TLRs) plays a major role in innate immunity by mediating inflammatory reactions against a wide array of pathogens. TLR-2 is reported to interact with various bacterial partial structures including lipoproteins, peptidoglycan, and lipoteichoic acid. Two polymorphisms of the TLR-2 gene have recently been described: Arg753Gln, correlated with the incidence of sepsis in a white population, and Arg677Trp, correlated with the incidence of lepromatous leprosy in an Asian population. Both polymorphisms, when inserted into expression vectors encoding for human TLR-2, reduced stimulation of Chinese hamster ovary cells by synthetic lipopeptides. We furthermore developed a rapid and inexpensive method for the detection of both single nucleotide polymorphisms based on restriction fragment length polymorphism. While no individuals carrying the Arg677Trp SNP were identified in a large group of whites, 9.4% of the study population were found to be heterozygous for the Arg753Gln polymorphism. This ratio is significantly higher than previously reported, and therefore detection of this polymorphism among patients may yield important information for the assessment of risk profiles regarding susceptibility to bacterial infections.
J Mol Med (Berl) 2003 Jun
PMID:High frequency of polymorphism Arg753Gln of the Toll-like receptor-2 gene detected by a novel allele-specific PCR. 1274 10

Leprosy is a chronic infectious disease caused by Mycobacterium leprae that mainly affects the skin and peripheral nerves. Over recent years, many important advances have been made in developing molecular diagnostics, in identifying highly effective drugs and designing multidrug regimens for treatment, and in unravelling the genomic structure and functions of the leprosy bacillus. Using the new information about specific sequences of M. leprae, several gene probes and gene amplification systems for confirming diagnosis and monitoring treatment have been developed. Among these, polymerase chain reaction (PCR)-based methods have been useful in confirming the diagnosis in paucibacillary leprosy (where few bacilli are present). RNA-targeting systems for monitoring the progress of treatment, in situ hybridisation techniques for analysing specimens with nonspecific histological features, and molecular methods for direct detection of rifampicin/dapsone resistance are other major technological advances with immense applied value. Several effective regimens for the treatment of leprosy have been developed, which include rifampicin, clofazimine and dapsone as core drugs. Although these regimens are generally satisfactory, limitations in terms of persisting activity and late reactions/relapses in paucibacillary leprosy, and persistence of dead and/or live organisms in multibacillary forms of the disease, have been observed.
Expert Rev Mol Med 2002 Jul 22
PMID:Advances in the diagnosis and treatment of leprosy. 1458 55

The production of the type I antimicrobial peptide (AMP) subtilin by Bacillus subtilis is regulated in a cell-density-dependent manner [Kleerebezem M, de Vos WM, Kuipers OP. The lantibiotics nisin and subtilin act as extracellular regulators of their own biosynthesis. In: Dunny GM, Winans SC, editors. Cell-cell signaling in bacteria. Washington, D.C., USA: ASM Press; 1999. p. 159-74; Stein T, Borchert S, Kiesau P, Heinzmann S, Kloss S, Klein C, Helfrich M, Entian KD. Dual control of subtilin biosynthesis and immunity in Bacillus subtilis. Mol Microbiol 2002;44:403-16; Stein T, Heinzmann S, Kiesau P, Himmel B, Entian KD. The spa-box for transcriptional activation of subtilin biosynthesis and immunity in Bacillus subtilis. Mol Microbiol 2003;47:1627-36]. Three subtilin-responsive promoter elements within the spaBTCSIFEGRK are controlled by the specific cis-acting sequence element called the spa-box, which represents the binding site of the subtilin regulator SpaR [Stein T, Heinzmann S, Kiesau P, Himmel B, Entian KD. The spa-box for transcriptional activation of subtilin biosynthesis and immunity in Bacillus subtilis. Mol Microbiol 2003;47:1627-36]. Here, we describe the functional characterization of the spaB, spaS and spaI promoters by transcriptional fusion with a promoterless beta-glucuronidase encoding gusA gene. Within these gusA fusion constructs, transcription initiation start sites of the spaS and spaI promoters were mapped to be located downstream of the spa-box, which is in contrast to previous reports [Banerjee S, Hansen JN. Structure and expression of a gene encoding the precursor of subtilin, a small protein antibiotic. J Biol Chem 1988;263:9508-14; Stein T, Heinzmann S, Kiesau P, Himmel B, Entian KD. The spa-box for transcriptional activation of subtilin biosynthesis and immunity in Bacillus subtilis. Mol Microbiol 2003;47:1627-36]. Nevertheless, all spa-promoters displayed typical cell-density-dependent activity in a subtilin-producing strain B. subtilis ATCC6633. Moreover, analysis of beta-glucuronidase activities in a spaB mutant of B. subtilis ATCC6633 and a derivative of strain 168 that harbors the spaRK genes integrated in the chromosomal amyE locus, confirmed that these promoters are activated by subtilin-triggered, SpaRK-mediated, quorum-sensing control. Quantitative analysis showed that the spaS promoter strength at a given subtilin concentration appeared to be approximately five-fold higher than the spaB promoter, which in turn is approximately two-fold higher than the spaI promoter. Finally, it is shown that the elementary components involved in subtilin-mediated regulation are the two-component system, SpaRK, and a spa-box containing promoter.
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PMID:Autoregulation of subtilin biosynthesis in Bacillus subtilis: the role of the spa-box in subtilin-responsive promoters. 1537 45

While formaldehyde fixation preserves tissue morphology, it often hinders immunodetection of antigens in paraffin-embedded tissue because the antigens are masked. Antigen unmasking can be achieved with treatments such as microwave irradiation but they often lead to excessive tissue damage. Therefore, an electrochemical antigen-retrieval method (EAR) was devised in which an alternating electric current is passed through the tissue in a chamber containing an electrolyte buffer. The results obtained with this method were compared to those after microwave irradiation using archived samples of formaldehyde-fixed and paraffin-embedded lepromatous leprosy skin. The efficacy of the two unmasking procedures was assessed by the immunodetectability of several marker antigens using 24 antibodies. Fifteen antibodies that were directed against transmembrane proteins (CD), and the remaining 9 against cytokeratins 18.6 and 19, laminin, vimentin, S100a, BCG, Ulex europaeus lectin, PCNA, and P21ras. Simple and double immunohistochemistry was performed using the universal ENVISION and LSAB + AP detection systems. After unmasking with the EAR method, immunoreactivity was clearly detected with 22 of the 24 antibodies in single labeling reactions. They include the critical antigens CD3 and CD4 for identifying the T lymphocyte lineages. In contrast, only 20 of the antibodies reacted after microwave irradiation. After double immunolabeling, immunoreactivity was quantitatively similar with both methods. However, the EAR unmasking produced a stronger labeling reaction. Thus, with double labeling immunohistochemistry, EAR made it possible to use higher antibody dilutions and shorter incubation times. Heat damage was also prevented. In conclusion, EAR treatment produces better staining results than microwave irradiation treatment.
J Mol Histol 2004 Jun
PMID:Electrochemical antigen-retrieval of formaldehyde fixed and paraffin-embedded archived leprosy skin biopsies. 1557 21

The genome of Mycobacterium leprae, the etiologic agent of leprosy, has been sequenced and annotated revealing a genome in apparent disarray and in stark contrast to the genome of the related human pathogen, M. tuberculosis. With less than 50% coding capacity of a 3.3-Mb genome and 1,116 pseudogenes, the remaining genes help define the minimal gene set necessary for in vivo survival of this mycobacterial pathogen as well as genes potentially required for infection and pathogenesis seen in leprosy. To identify genes transcribed during infection, we surveyed gene transcripts from M. leprae growing in athymic nude mice using reverse transcriptase-polymerase chain reaction (RT-PCR) and cross-species DNA microarray technologies. Transcripts were detected for 221 open reading frames, which included genes involved in DNA replication, cell division, SecA-dependent protein secretion, energy production, intermediary metabolism, iron transport and storage and genes associated with virulence. These results suggest that M. leprae actively catabolizes fatty acids for energy, produces a large number of secretory proteins, utilizes the full array of sigma factors available, produces several proteins involved in iron transport, storage and regulation in the absence of recognizable genes encoding iron scavengers and transcribes several genes associated with virulence in M. tuberculosis. When transcript levels of 9 of these genes were compared from M. leprae derived from lesions of multibacillary leprosy patients and infected nude mouse foot pad tissue using quantitative real-time RT-PCR, gene transcript levels were comparable for all but one of these genes, supporting the continued use of the foot pad infection model for M. leprae gene expression profiling. Identifying genes associated with growth and survival during infection should lead to a more comprehensive understanding of the ability of M. leprae to cause disease.
J Mol Microbiol Biotechnol 2004
PMID:Biological implications of Mycobacterium leprae gene expression during infection. 1574 41


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