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)

Pulmonary lymphangioleiomyomatosis (LAM) is characterized by abnormal smooth muscle-like cell (LAM cell) proliferation leading to tissue destruction. We previously demonstrated that serum response factor (SRF), a critical smooth muscle transcription factor, is highly expressed in LAM cells. Here we show that a high SRF level alters the plasminogen (Plg) system. Specifically, overexpression of SRF in human lung fibroblasts upregulated urokinase-type plasminogen activator (uPA) and its substrate Plg, whereas it downregulated plasminogen activator inhibitor (PAI)-1. Because uPA cleaves Plg into plasmin, which activates matrix metalloproteinases (MMP), the end result was an increase in MMP activity. To determine whether uPA, Plg, and PAI-1 were abnormally expressed in LAM in vivo, we immunostained 12 LAM cases. In all cases, the LAM lesions showed stronger immunoreaction for uPA and Plg than the surrounding normal lung parenchyma. On the contrary, PAI-1 was absent in LAM lesions, whereas it was ubiquitous in normal lung parenchyma. Microdissection-based reverse transcriptase/polymerase chain reaction further confirmed upregulation of uPA and Plg and downregulation of PAI-1 message in LAM. Altogether, our findings suggest that the high SRF level seen in LAM contributes to extracellular matrix degradation and progressive LAM cell infiltration of the lung.
Am J Respir Cell Mol Biol 2005 Jan
PMID:Imbalanced plasminogen system in lymphangioleiomyomatosis: potential role of serum response factor. 1551 13

Two HIV-1-infected children on antiretroviral therapy were enrolled into a clinical study of retroviral-mediated transfer of a gene that inhibits replication of HIV-1, targeting bone marrow CD34+ hematopoietic stem/progenitor cells. Two retroviral vectors were used, one encoding a "humanized" dominant-negative REV protein (huM10) that is a potent inhibitor of HIV-1 replication and one encoding a nontranslated marker gene (FX) to serve as an internal control for the level of gene marking. Peripheral blood mononuclear cells (PBMC) containing the huM10 gene or FX gene were detected by quantitative PCR at frequencies of approximately 1/10,000 in both subjects for the first 1-3 months following re-infusion of the gene-transduced bone marrow, but then were at or below the limits of detection (<1/1,000,000) at most times over 2 years. In one patient, a reappearance of PBMC containing the huM10 gene, but not the FX gene, occurred concomitant with a rise in the HIV-1 viral load during a period of nonadherence to the antiretroviral regimen. Unique clones of gene-marked PBMC were detected by LAM-PCR during the time of elevated HIV-1 levels. These findings indicate that there was a selective survival advantage for PBMC containing the huM10 gene during the time of increased HIV-1 load.
Mol Ther 2005 Jul
PMID:Selective survival of peripheral blood lymphocytes in children with HIV-1 following delivery of an anti-HIV gene to bone marrow CD34(+) cells. 1596 23

Pulmonary lymphangioleiomyomatosis (LAM) and renal angiomyolipoma (AML) are proliferative lesions that occur in sporadic patients, and at much higher frequency in patients with tuberous sclerosis (TSC). The TSC1 and TSC2 genes play a critical role in their pathogenesis. Here we report a marked decrease in interferon (IFN)-gamma expression in both sporadic and TSC-associated AML and LAM. A marked increase in Stat1 expression and phosphorylation at Ser 727, and in phospho-Tyr705-Stat3 levels, was also seen in both AML and LAM tissues. Our results demonstrate that the IFN-gamma-Jak-Stat pathway is perturbed in TSC-related and sporadic LAM and AML, and suggest that IFN-gamma has potential therapeutic benefit for treatment of those lesions.
Am J Respir Cell Mol Biol 2005 Sep
PMID:Interferon-gamma-Jak-Stat signaling in pulmonary lymphangioleiomyomatosis and renal angiomyolipoma: a potential therapeutic target. 1599 29

Mycobacterium tuberculosis (M. tb) pathogenesis involves the interaction between the mycobacterial cell envelope and host macrophage, a process mediated, in part, by binding of the mannose caps of M. tb lipoarabinomannan (ManLAM) to the macrophage mannose receptor (MR). A presumed critical step in the biosynthesis of ManLAM, and other mannose-containing glycoconjugates, is the conversion of mannose-6-phosphate to mannose-1-phosphate, by a phosphomannomutase (PMM), to produce GDP-mannose, the primary mannose-donor in mycobacteria. We have identified four M. tb H37Rv genes with similarity to known PMMs. Using in vivo complementation of PMM and phosphoglucomutase (PGM) deficient strains of Pseudomonas aeruginosa, and an in vitro enzyme assay, we have identified both PMM and PGM activity from one of these genes, Rv3257c (MtmanB). MtmanB overexpression in M. smegmatis produced increased levels of LAM, lipomannan, and phosphatidylinositol mannosides (PIMs) compared with control strains and led to a 13.3 +/- 3.9-fold greater association of mycobacteria with human macrophages, in a mannan-inhibitable fashion. This increased association was mediated by the overproduction of higher order PIMs that possess mannose cap structures. We conclude that MtmanB encodes a functional PMM involved in the biosynthesis of mannosylated lipoglycans that participate in the association of mycobacteria with macrophage phagocytic receptors.
Mol Microbiol 2005 Nov
PMID:Overexpression of Mycobacterium tuberculosis manB, a phosphomannomutase that increases phosphatidylinositol mannoside biosynthesis in Mycobacterium smegmatis and mycobacterial association with human macrophages. 1623 26

The loss of TSC2 function is associated with the pathobiology of lymphangioleiomyomatosis (LAM), which is characterized by the abnormal proliferation, migration, and differentiation of smooth muscle-like cells within the lungs. Although the etiology of LAM remains unknown, clinical and genetic evidence provides support for the neoplastic nature of LAM. The goal of this study was to determine the role of tumor suppressor TSC2 in the neoplastic potential of LAM cells. We show that primary cultures of human LAM cells exhibit increased migratory activity and invasiveness, which is abolished by TSC2 re-expression. We found that TSC2 also inhibits cell migration through its N-terminus, independent of its GTPase-activating protein activity. LAM cells show increased stress fiber and focal adhesion formation, which is attenuated by TSC2 re-expression. The small GTPase RhoA is activated in LAM cells compared with normal human mesenchymal cells. Pharmacologic inhibition of Rho activity abrogates LAM cell migration; RhoA activity was also abolished by TSC2 re-expression or TSC1 knockdown with specific siRNA. These data demonstrate that TSC2 controls cell migration through its N-terminus by associating with TSC1 and regulating RhoA activity, suggesting that TSC2 may play a critical role in modulating cell migration and invasiveness, which contributes to the pathobiology of LAM.
Am J Respir Cell Mol Biol 2006 Apr
PMID:Modulation of cell migration and invasiveness by tumor suppressor TSC2 in lymphangioleiomyomatosis. 1638 22

The TSC1 and TSC2 proteins, which function as a TSC1/TSC2 tumor suppressor complex, are associated with lymphangioleiomyomatosis (LAM), a genetic disorder characterized by the abnormal growth of smooth muscle-like cells in the lungs. The precise molecular mechanisms that modulate LAM cell growth remain unknown. We demonstrate that TSC2 regulates LAM cell growth. Cells dissociated from LAM nodules from the lungs of five different patients with LAM have constitutively activated S6K1, hyperphosphorylated ribosomal protein S6, activated Erk, and increased DNA synthesis compared with normal cells from the same patients. These effects were augmented by PDGF stimulation. Akt activity was unchanged in LAM cells. Rapamycin, a specific S6K1 inhibitor, abolished increased LAM cell growth. The full-length TSC2 was necessary for inhibition of S6 hyperphosphorylation and DNA synthesis in LAM cells, as demonstrated by co-microinjection of the C-terminus, which contains the GTPase activating protein homology domain, and the N-terminus, which binds TSC1. Our data demonstrate that increased LAM cell growth is associated with constitutive S6K1 activation, which is extinguishable by TSC2 expression. Loss of TSC2 GAP activity or disruption of the TSC1/TSC2 complex dysregulates S6K1 activation, which leads to abnormal cell proliferation associated with LAM disease.
Am J Respir Cell Mol Biol 2006 May
PMID:Abnormal growth of smooth muscle-like cells in lymphangioleiomyomatosis: Role for tumor suppressor TSC2. 1642 83

Lymphangioleiomyomatosis (LAM), a multisystem disease found in middle-aged women, is characterized by cystic lung destruction and abdominal tumors (e.g., angiomyolipomas, lymphangioleimyomas), resulting from proliferation of abnormal-appearing, smooth muscle-like cells (LAM cells). The LAM cells, in combination with other cells, form nodular structures within the lung interstitium and in the walls of the cysts. LAM cells contain mutations in the tuberous sclerosis complex TSC1 and/or TSC2 genes, which lead to dysregulation of the mammalian target of rapamycin, affecting cell growth and proliferation. Proliferation and migration of vascular smooth muscle cells and production of angiogenic factors are regulated, in part, by angiotensin II. To determine whether a LAM-specific renin-angiotensin system might play a role in the pathogenesis of LAM, we investigated the expression of genes and gene products of this system in LAM nodules. mRNA for angiotensinogen was present in RNA isolated by laser-captured microdissection from LAM nodules. Angiotensin I-converting enzyme and chymase-producing mast cells were present within the LAM nodules. We detected renin in LAM cells, as determined by the presence of mRNA and immunohistochemistry. Angiotensin II type 1 and type II receptors were identified in LAM cells by immunohistochemistry and immunoblotting of microdissected LAM nodules. Angiotensin II is localized in cells containing alpha-smooth muscle actin (LAM cells). A LAM-specific renin-angiotensin system appears to function within the LAM nodule as an autocrine system that could promote LAM cell proliferation and migration, and could represent a pharmacologic target.
Am J Respir Cell Mol Biol 2006 Jul
PMID:Tissue-specific renin-angiotensin system in pulmonary lymphangioleiomyomatosis. 1647 96

The Mycobacterium tuberculosis strains of genotype A1 (LAM family, VNTR profile 222222) are often resulted from people with pulmonary tuberculosis, who live in Central Russia. Among strains of this family, drug-resistant strains, including those with simultaneous resistance to isoniazid and rifampicin (MDR), are common. The strains of the genotype A1 tend to spread as clones.
Mol Gen Mikrobiol Virusol 2006
PMID:[Characteristics of Mycobacterium tuberculosis clinical strains genotype A1]. 1675

The potential of in vivo lentivirus-mediated bone marrow stem cell gene transfer by bone cavity injection, which could take full advantage of any source of stem cells present there, has not been previously explored. Such an approach may avoid several difficulties encountered by ex vivo hematopoietic stem cell (HSC) gene transfer. We sought to determine if efficient gene transfer could be achieved in HSC and mesenchymal stem/progenitor cells (MSC) by intrafemoral injection of a lentivirus vector in mice. Four months after injection, up to 12% GFP-expressing cells were observed in myeloid and lymphoid subpopulations. Significant transduction efficiencies were seen in Lin(-)c-kit(+)Sca1(+) HSC/progenitors and CFU with multilineage potential, which were also confirmed by duplex PCR analysis of progenitor-derived colonies. Four months after secondary BMT, we observed 8.1 to 15% vector(+) CFU in all recipients. Integration analysis by LAM-PCR demonstrated that multiple transduced clones contributed to hematopoiesis in these animals. We also showed that GFP-expressing MSC retained multilineage differentiation potential, with 2.9 to 8.8% GFP-containing CFU-fibroblasts detected in both injected and BMT recipients. Our data provide evidence that adult stem cells in bone marrow can be efficiently transduced "in situ" by in vivo vector administration without preconditioning. This approach could lead to a novel application for treatment of human diseases.
Mol Ther 2006 Oct
PMID:In vivo gene transfer into adult stem cells in unconditioned mice by in situ delivery of a lentiviral vector. 1689 84

The products of the tuberous sclerosis complex (TSC) genes, hamartin and tuberin (TSC1 and 2), form a heteromer, which represses the kinase mammalian target of rapamycin. Loss of TSC1 or 2 results in diseases characterized by loss of cell-cycle control, including TSC and lymphangioleiomyomatosis. As tuberin has multiple signaling inputs, including phosphatidylinositide-3-OH kinase, mitogen-activated protein kinase, and adenosine monophosphate kinase, we postulated tuberin would have multiple protein interactions governed by subcellular localization and cellular status and examined this in primary human airway smooth muscle cells. Using immunofluorescence and confocal microscopy, tuberin was detected in cytoplasm, nucleus, nucleoli, and mitochondria. Fractionation of synchronized airway smooth cells showed that tuberin enters the nucleus in late G(1), and passage through the cell cycle is necessary for nuclear entry. Deletion constructs showed localization sequences for the nucleus between amino acids 1351 and 1807, for mitochondria between 901 and 1350, and for cytoplasmic speckles between 1 and 450. Using fluorophore-tagged proteins, we observed fluorescence resonance energy transfer between tuberin and hamartin within these speckles, indicating a direct interaction between the proteins at this site. The observations that tuberin is localized to mitochondria and translocated to the nucleus in G(1) are novel and consistent with interactions with proteins within multiple signaling pathways. Dynamic relocalization of tuberin may control these interactions to integrate these pathways. As tuberin has potential roles in proliferation, migration, and cell phenotype, it therefore warrants further investigation in diseases categorized by abnormalities in airway smooth muscle.
Am J Physiol Lung Cell Mol Physiol 2007 Jan
PMID:Subcellular distribution of the TSC2 gene product tuberin in human airway smooth muscle cells is driven by multiple localization sequences and is cell-cycle dependent. 1690 38


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