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)

Elastin, an extracellular component of arteries, lung, and skin, is produced during fetal and neonatal growth. We reported previously that the cessation of elastin production is controlled by a posttranscriptional mechanism. Although tropoelastin pre-mRNA is transcribed at the same rate in neonates and adults, marked instability of the fully processed transcript bars protein production in mature tissue. Using RNase protection, we identified a 10-nucleotide sequence in tropoelastin mRNA near the 5' end of the sequences coded by exon 30 that interacts specifically with a developmentally regulated cytosolic 50-kDa protein. Binding activity increased as tropoelastin expression dropped, being low in neonatal fibroblasts and high in adult cells, and treatment with transforming growth factor beta1 (TGF-beta1), which stimulates tropoelastin expression by stabilizing its mRNA, reduced mRNA-binding activity. No other region of tropoelastin mRNA interacted with cellular proteins, and no binding activity was detected in nuclear extracts. The ability of the exon-30 element to control mRNA decay and responsiveness to TGF-beta1 was assessed by three distinct functional assays: (i) insertion of exon 30 into a heterologous gene conferred increased reporter activity after exposure to TGF-beta1; (ii) addition of excess exon 30 RNA slowed tropoelastin mRNA decay in an in vitro polysome degradation assay; and (iii) a mutant tropoelastin cDNA lacking exon 30, compared to wild-type cDNA, produced a stable transcript whose levels were not affected by TGF-beta1. These findings demonstrate that posttranscriptional regulation of elastin production in mature tissue is conferred by a specific element within the open reading frame of tropoelastin mRNA.
Mol Cell Biol 1999 Nov
PMID:An open reading frame element mediates posttranscriptional regulation of tropoelastin and responsiveness to transforming growth factor beta1. 1052 20

A two-helix version of the triple alpha-helical staphylococcal Protein A, previously shown to retain the Fc binding properties of protein A, has been engineered to contain an elastin sequence, GVPGVG, within the inter-helix turn. The original type I beta-turn was replaced with a beta-turn from the muscle protein elastin, which has an inverse temperature-induced folding transition. These "elastin mutants" had lost their helical structure, as measured by circular dichroism (CD), and exhibited a lower stability than the wild-type domains (T(m) reduced by about 48 degrees C) in 30% trifluoroethanol. For the wild-type domains, the amount of alpha-helix and the binding affinity for Fc decreased as the temperature was increased. In contrast, although the starting affinity was lower for the disulfide elastin-turn mutant, it exhibited a 21-fold improvement in affinity over the same temperature range. The melting curve for the elastin-turn minidomain showed cooperative behavior, as measured by the increase in CD-amplitude at 222 nm. The observed CD behavior is consistent with the formation of a type I beta-turn, exhibiting similar DeltaH and DeltaS values to those seen previously for short elastin peptides [Reiersen, H., Clarke, A. R., and Rees, A. R. (1998) J. Mol. Biol. 283, 255-264], and accounting for the increase in on-rate. This demonstrates that, when inserted into a stable globular protein, short elastin sequences have the ability to modify local structure and activity, by operating as temperature modulated switches.
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PMID:An engineered minidomain containing an elastin turn exhibits a reversible temperature-induced IgG binding. 1055 72

Elastic fibers consist of two morphologically distinct components: elastin and 10-nm fibrillin-containing microfibrils. During development, the microfibrils form bundles that appear to act as a scaffold for the deposition, orientation, and assembly of tropoelastin monomers into an insoluble elastic fiber. Although microfibrils can assemble independent of elastin, tropoelastin monomers do not assemble without the presence of microfibrils. In the present study, immortalized ciliary body pigmented epithelial (PE) cells were investigated for their potential to serve as a cell culture model for elastic fiber assembly. Northern analysis showed that the PE cells express microfibril proteins but do not express tropoelastin. Immunofluorescence staining and electron microscopy confirmed that the microfibril proteins produced by the PE cells assemble into intact microfibrils. When the PE cells were transfected with a mammalian expression vector containing a bovine tropoelastin cDNA, the cells were found to express and secrete tropoelastin. Immunofluorescence and electron microscopic examination of the transfected PE cells showed the presence of elastic fibers in the matrix. Biochemical analysis of this matrix showed the presence of cross-links that are unique to mature insoluble elastin. Together, these results indicate that the PE cells provide a unique, stable in vitro system in which to study elastic fiber assembly.
Mol Biol Cell 1999 Nov
PMID:Characterization of an in vitro model of elastic fiber assembly. 1056 58

The promoter activity of lysyl oxidase (LOX), the enzyme involved in collagen and elastin cross-linking and in tumor suppression, was compared in extracellular matrix producing cells and in tumorigenic c-Ha-ras-NIH-3T3 fibroblasts (RS485). The full 2 kb murine LOX promoter was very active in 3T6-5 myofibroblast-like cells (MFLC) and vascular smooth muscle cells (SMC) and was inhibited in ras-transformed fibroblasts. Positive cis-acting elements were located around sites of transcription initiation in MFLC and SMC, but neither in RS485 fibroblasts nor in their non-transformed counterparts. The main positive cis-acting segment, at positions -808 to -585, was active in all cells, with the strongest activity in MFLC and SMC, and one segment, at positions -758 to -726, allowed the formation of one master DNA-protein complex with nuclear factors from all cells. The main inhibiting region, at positions -1,362 to -1,176, was active in all fibroblasts, but not in SMC, in an upstream position or in an enhancer/silencer position. This region carries two segments, called LOcoll and LOcol2 for their similarity to COL1A1 and COL1A2 promoter sequences, that were involved in the formation of a large multifactorial DNA complex with nuclear factors from all cells, though slightly for SMC. Another region, carrying a putative interferon response element (IRF) at positions -898 to -886, acted negatively on each type of cells. In conclusion, the LOX promoter is controlled by cross-talk between positive and negative cis-acting regions that are differentially active in various cells. The -758 to -726 region, with its putative C/EBP site, and the transcription initiation region are likely to play a master role in activating the LOX promoter in fibrocompetent MFLC and SMC. While the LOcol1/2 segment, with putative B-Myb binding sites, and the IRF carrying region, work negatively on the LOX promoter in transformed cells.
Cell Mol Biol (Noisy-le-grand) 1999 Dec
PMID:Comparative functional study of the lysyl oxidase promoter in fibroblasts, Ras-transformed fibroblasts, myofibroblasts and smooth muscle cells. 1064 73

Recent studies have suggested that macrophage-derived metalloproteases are the critical mediators of cigarette smoke-induced emphysema, in contrast to earlier hypotheses that this process was mediated by neutrophil elastase. To determine whether smoke can acutely induce connective tissue breakdown in the lung and to examine the mediators of this process, we exposed C57-BL/6 mice to whole cigarette smoke and used high-performance liquid chromatography to examine lavage fluid levels of desmosine (DES), a marker of elastin breakdown, and hydroxyproline (HP), a marker of collagen breakdown. Smoke produced a dose-response increase in lavage neutrophils, DES, and HP, but not lavage macrophages (MACs). This effect was evident by 6 h after exposure to two cigarettes. Pretreatment with an antibody against polymorphonuclear leukocytes (PMNs) reduced lavage PMNs to undetectable levels after smoke exposure, did not affect MAC numbers, and prevented increases in lavage DES and HP. Intraperitoneal injection of a commercial human alpha1-antitrypsin (alpha1AT) 24 h before smoke exposure increased serum alpha1AT levels approximately 3-fold and completely abolished smoke-induced connective tissue breakdown as well as the increase in lavage PMNs, again without affecting MAC numbers. We conclude that in this model cigarette smoke can acutely induce connective tissue breakdown and that this effect is mediated by neutrophil-derived serine proteases, most likely neutrophil elastase. Exogenous alpha1AT is protective and appears to inhibit both matrix degradation and PMN influx, suggesting that alpha1AT has anti-inflammatory as well as antiproteolytic effects in this system.
Am J Respir Cell Mol Biol 2000 Feb
PMID:Acute cigarette smoke-induced connective tissue breakdown is mediated by neutrophils and prevented by alpha1-antitrypsin. 1065 46

The airway basement membrane zone is a region specialized for the attachment of the epithelium with the matrix. The epithelium is attached to the lamina densa, which, in turn, is connected to types I and III collagen of the lamina reticularis with anchoring fibrils. The purpose of this study was to define the three-dimensional organization of the structural proteins of the lamina reticularis in the rat trachea. We approached this problem by using whole mounts to look down on the flat surface of the basement-membrane zone rather than a cross section of its thin profile. Fluorescent microscopy with long working distance water immersion objectives and scanning electron microscopy revealed that the structural proteins are arranged as a mat of large fibers oriented along the longitudinal axis of the airway. Smaller fibers are crosslinked with the larger fibers to complete this structure. Other small fibers are oriented around the large fibers and an amorphous material covers individual fibers. The large fibers oriented along the longitudinal axis of the airway are consistent with prior descriptions of fibers composed of collagen III with some collagen I and V; small fibers encircling the large fibers may be collagen VI. The crosslinking fibers are made up of elastin and probably elastin-associated microfibrils. The amorphous proteins covering the fibrous framework may contain proteoglycans and other nonstructural proteins reported to be in the lamina reticularis. The present studies demonstrate that the structural proteins of the lamina reticularis in the rat trachea are arranged as fibers in a highly organized manner.
Am J Respir Cell Mol Biol 2000 Apr
PMID:Three-dimensional organization of the lamina reticularis in the rat tracheal basement membrane zone. 1074 18

Latent transforming growth factor beta (TGF-beta) binding protein 2 (LTBP-2) is an integral component of elastin-containing microfibrils. We studied the expression of LTBP-2 in the developing mouse and rat by in situ hybridization, using tropoelastin expression as a marker of tissues participating in elastic fiber formation. LTBP-2 colocalized with tropoelastin within the perichondrium, lung, dermis, large arterial vessels, epicardium, pericardium, and heart valves at various stages of rodent embryonic development. Both LTBP-2 and tropoelastin expression were seen throughout the lung parenchyma and within the cortex of the spleen in the young adult mouse. In the testes, LTBP-2 expression was seen within lumenal cells of the epididymis in the absence of tropoelastin. Collectively, these results imply that LTBP-2 plays a structural role within elastic fibers in most cases. To investigate its importance in development, mice with a targeted disruption of the Ltbp2 gene were generated. Ltbp2(-/-) mice die between embryonic day 3.5 (E3.5) and E6.5. LTBP-2 expression was not detected by in situ hybridization in E6.5 embryos but was detected in E3.5 blastocysts by reverse transcription-PCR. These results are not consistent with the phenotypes of TGF-beta knockout mice or mice with knockouts of other elastic fiber proteins, implying that LTBP-2 performs a yet undiscovered function in early development, perhaps in implantation.
Mol Cell Biol 2000 Jul
PMID:Developmental expression of latent transforming growth factor beta binding protein 2 and its requirement early in mouse development. 1084 13

We have shown that dexamethasone (Dex) accelerates maturation and differentiation of cultured fetal murine lungs (Cilley RE, Zgleszewski SE, Krummel TM, and Chinoy MR. Surg Forum 47: 692-695, 1996). We now demonstrate that although Dex inhibits thinning of acinar walls and secondary septa formation, it does, however, promote lung growth. CD-1 murine fetal lungs were cultured for 7 days in the presence and absence of 10 nM Dex. Dex-modulated genes were investigated and identified by differential display of mRNAs performed with specific anchor primer H-T(11)G and 24 arbitrary primers. Thirty-five differentially expressed cDNAs were isolated, subcloned, sequenced, and identified through BLAST searches. One of these cDNAs, termed Dex2, with enhanced expression in Dex-treated lungs, had 100% similarity with ras-recision gene (rrg), also known as the lysyl oxidase (LOX) gene that encodes lysyl oxidase. LOX gene is very highly conserved, with significant sequence similarity among mouse, rat, and human. Two other cDNAs, termed Dex1 and Dex4, were also identified as rrg, with 92 and 97% sequence similarity with the existing data bank sequence of rrg. LOX enzyme is known to downregulate p21(ras) protein and play a central role in the maturation of collagen and elastin in the extracellular matrix as well as modulate the cytoskeletal elements. Thus LOX may be important in lung developmental processes involving epithelial-mesenchymal interactions.
Am J Physiol Lung Cell Mol Physiol 2000 Aug
PMID:Dexamethasone enhances ras-recision gene expression in cultured murine fetal lungs: role in development. 1092 54

Elastin is a major component of the mammalian lung, predominantly found in the alveoli. Destruction of alveolar elastic fibers is implicated in the pathogenic mechanism of emphysema in adults. These data define a role for elastin in the structure and function of the mature lung, and suggest that elastin is important for alveogenesis. To investigate the role of elastin in lung development, we examined mice lacking elastin (Eln-/-). At birth, the distal air sacs of Eln-/- lungs dilate to form abnormally large cavities. This phenotype appears before the synthesis and deposition of alveolar elastin, a process mediated by myofibroblasts and initiated after postnatal Day 4. Morphometric analyses demonstrate that the perinatal development of terminal airway branches is arrested in Eln-/- mice. The branching defect is accompanied by fewer distal air sacs that are dilated with attenuated tissue septae, a condition reminiscent of emphysema. Elastin expression in the lung parenchyma before alveogenesis is localized to the mesenchyme surrounding the developing airways, supporting a role for elastin in airway branching. Thus, in addition to its role in the structure and function of the mature lung, elastin is essential for pulmonary development and is important for terminal airway branching.
Am J Respir Cell Mol Biol 2000 Sep
PMID:Impaired distal airway development in mice lacking elastin. 1097 Aug 22

The expression of each locus in our genome is regulated by a gene-potentiative mechanism, whereby the gene first assumes the necessary structural conformation to enable transcription. This serves as the corner-stone for the three-tiered regulatory mechanism of potentiation, i.e., the opening of a chromatin domain, initiation of transcription, and transcript elongation. Although this is now generally accepted as the pathway that mediates gene expression, it has never been shown directly to control the expression of any heart-related gene. Lysyl oxidase enzymatically crosslinks members of the extracellular matrix, including elastin and collagen. Formation of these structures is essential to development and tissue repair. This system has enabled us to begin to address the underlying mechanism governing the selection of connective tissue genes for expression. However, before one can dissect this mechanism, it is necessary to define and characterize the locus, i.e., the corresponding genic domain. Our progress toward creating the resources necessary to unravel this mechanism is summarized in this review.
Mol Biotechnol 2000 Jul
PMID:Characterizing a human lysyl oxidase chromosomal domain. 1098 98


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