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PubMed1995

Cell cycle-dependent regulation of elastin gene in cultured chick vascular smooth-muscle cells.

A study was made of the relationship between elastin expression and the proliferative state of chick vascular smooth-muscle cells. Confluent cells of primary culture brought to a quiescent state by the deprivation of serum for 72 h exhibited a 5-, 3.5- and 2-fold increase in elastin synthesis, elastin mRNA level and transcriptional activity of elastin gene respectively over those in the proliferative state. On re-addition of serum in serum-deprived culture, cells started to proliferate, and elastin synthesis, its mRNA level and transcription of the gene decreased to the level of a proliferative state within 24 h, indicating that elastin expression in smooth-muscle cells was controlled by their growth states at least in part at a transcriptional level. A comparable increase in elastin mRNA level was observed when the cell growth was arrested by suspension culture for 72 h. When the cells were synchronized at the G1/S phase with thymidine/hydroxyurea treatment, elastin expression at the G1/S phase was greater than that at the G2/M phase during cell cycling. Elastin mRNA level at the G0 phase brought about by serum-deprivation or suspension culture predominated over that at the G1/S phase during cell cycling. These results indicate that gene expression of elastin and cell cycle are tightly coupled, which is independent of the presence of serum or adhesive state, and that elastin expression could be a biochemical marker for the growth states of smooth-muscle cells.

Animals↗

PubMed2000

Conformational dependence of collagenase (matrix metalloproteinase-1) up-regulation by elastin peptides in cultured fibroblasts.

We have established that treatment of cultured human skin fibroblasts with tropoelastin or with heterogenic peptides, obtained after organo-alkaline or leukocyte elastase hydrolysis of insoluble elastin, induces a high expression of pro-collagenase-1 (pro-matrix metalloproteinase-1 (pro-MMP-1)). The identical effect was achieved after stimulation with a VGVAPG synthetic peptide, reflecting the elastin-derived domain known to bind to the 67-kDa elastin-binding protein. This clearly indicated involvement of this receptor in the described phenomenon. This notion was further reinforced by the fact that elastin peptides-dependent MMP-1 up-regulation has not been demonstrated in cultures preincubated with 1 mm lactose, which causes shedding of the elastin-binding protein and with pertussis toxin, which blocks the elastin-binding protein-dependent signaling pathway involving G protein, phospholipase C, and protein kinase C. Moreover, we demonstrated that diverse peptides maintaining GXXPG sequences can also induce similar cellular effects as a "principal" VGVAPG ligand of the elastin receptor. Results of our biophysical studies suggest that this peculiar consensus sequence stabilizes a type VIII beta-turn in several similar, but not identical, peptides that maintain a sufficient conformation to be recognized by the elastin receptor. We have also established that GXXPG elastin-derived peptides, in addition to pro-MMP-1, cause up-regulation of pro-matrix metalloproteinase-3 (pro-stromelysin 1). Furthermore, we found that the presence of plasmin in the culture medium activated these MMP proenzymes, leading to a consequent degradation of collagen substrate. Our results may be, therefore, relevant to pathobiology of inflammation, in which elastin-derived peptides bearing the GXXPG conformation (created after leukocyte-dependent proteolysis) bind to the elastin receptor of local fibroblasts and trigger signals leading to expression and activation of MMP-1 and MMP-3, which in turn exacerbate local connective tissue damage.

Cells, Cultured↗

PubMed2002

Connection between elastin haploinsufficiency and increased cell proliferation in patients with supravalvular aortic stenosis and Williams-Beuren syndrome.

To elucidate the pathomechanism leading to obstructive vascular disease in patients with elastin deficiency, we compared both elastogenesis and proliferation rate of cultured aortic smooth-muscle cells (SMCs) and skin fibroblasts from five healthy control subjects, four patients with isolated supravalvular aortic stenosis (SVAS), and five patients with Williams-Beuren syndrome (WBS). Mutations were determined in each patient with SVAS and in each patient with WBS. Three mutations found in patients with SVAS were shown to result in null alleles. RNA blot hybridization, immunostaining, and metabolic labeling experiments demonstrated that SVAS cells and WBS cells have reduced elastin mRNA levels and that they consequently deposit low amounts of insoluble elastin. Although SVAS cells laid down approximately 50% of the elastin made by normal cells, WBS cells deposited only 15% of the elastin made by normal cells. The observed difference in elastin-gene expression was not caused by a difference in the stability of elastin mRNA in SVAS cells compared with WBS cells, but it did indicate that gene-interaction effects may contribute to the complex phenotype observed in patients with WBS. Abnormally low levels of elastin deposition in SVAS cells and in WBS cells were found to coincide with an increase in proliferation rate, which could be reversed by addition of exogenous insoluble elastin. We conclude that insoluble elastin is an important regulator of cellular proliferation. Thus, the reduced net deposition of insoluble elastin in arterial walls of patients with either SVAS or WBS leads to the increased proliferation of arterial SMCs. This results in the formation of multilayer thickening of the tunica media of large arteries and, consequently, in the development of hyperplastic intimal lesions leading to segmental arterial occlusion.

Adolescent↗

PubMed2005

Overexpression of elastin fragments in infarcted myocardium attenuates scar expansion and heart dysfunction.

Ventricular dilation after myocardial infarction can cause heart failure. Increasing strength and elasticity in the infarct region might prevent ventricular dilation. Because elastin provides strength, extensibility, and resilience to tissues and maintains tissue architecture, we studied the effect of elastin expression in the infarct on scar expansion and heart function. COS-7 cells transfected with a plasmid with an elastin gene fragment or a vector were seeded into a Gelfoam mesh and cultured. Mechanical stretch test (n = 5/group) showed that the elastin mesh was more elastic (P < 0.05) and tensile (P < 0.05) than the vector mesh. In an in vivo study in rats, 6 days after left anterior descending coronary artery ligation, COS-7 cells (Cell group, n = 7) or COS-7 cells with elastin gene (Elastin group, n = 9) or vector (Vector group, n = 9) were transplanted into the infarct; infarcted rats served as controls (n = 7). Over 8 wk the Cell group did not demonstrate effects on scar expansion and deterioration of heart function vs. controls. In contrast, infarct expansion was smaller and heart function was better maintained in the Elastin group vs. the Vector group (P < 0.05). At 8 wk after cell transplantation Langendorff data showed that the Elastin group had greater (P < 0.01) developed pressure and a smaller left ventricular volume than the Vector group. Western blot and histology showed accumulated elastin in the Elastin group infarct. Changing the extracellular matrix composition of a myocardial infarct by increasing elastin fragment content attenuated scar expansion, ventricular dilation, and onset of heart dysfunction.

Animals↗

PubMed2007

Activation of elastin transcription by transforming growth factor-beta in human lung fibroblasts.

Elastin synthesis is essential for lung development and postnatal maturation as well as for repair following injury. Using human embryonic lung fibroblasts that express undetectable levels of elastin as assessed by Northern analyses, we found that treatment with exogenous transforming growth factor-beta (TGF-beta) induced rapid and transient increases in levels of elastin heterogeneous nuclear RNA (hnRNA) followed by increases of elastin mRNA and protein expression. In fibroblasts derived from transgenic mice, TGF-beta induced increases in the expression of a human elastin gene promoter fragment driving a chloramphenicol acetyl transferase reporter gene. The induction of elastin hnRNA and mRNA expression by TGF-beta was abolished by pretreatments with TGF-beta receptor I inhibitor, global transcription inhibitor actinomycin D, and partially blocked by addition of protein synthesis inhibitor cycloheximide, but was not affected by the p44/42 MAPK inhibitor U0126. Pretreatment with the p38 MAPK inhibitor SB-203580 also partially attenuated the levels of TGF-beta-induced elastin mRNA but not its hnRNA. Western analysis indicated that TGF-beta stimulated Akt phosphorylation. Inhibition of phosphatidylinositol 3-kinase and Akt phosphorylation by LY-294002 abolished TGF-beta-induced increases in elastin hnRNA and mRNA expression. Treatment of lung fibroblasts with interleukin-1beta or the histone deacetylase inhibitor trichostatin A inhibited TGF-beta-induced elastin mRNA and hnRNA expression by a mechanism that involved inhibition of Akt phosphorylation. Downregulation of Akt2 but not Akt1 expression employing small interfering RNA duplexes blocked TGF-beta-induced increases of elastin hnRNA and mRNA levels. Together, our results demonstrated that TGF-beta activates elastin transcription that is dependent on phosphatidylinositol 3-kinase/Akt activity.

Cells, Cultured↗

PubMed1994

Ozone, but not nitrogen dioxide, fragments elastin and increases its susceptibility to proteolysis.

The effects of ozone (O3) and nitrogen dioxide (NO2) on the solubility and proteolytic susceptibility of elastin were examined to better understand how these oxidant air pollutants might damage the lung. In vitro O3 exposures at pH 7.4 resulted in the complete solubilization of elastin, but NO2 had no effect on solubility. The initial solubilization rate was 65 micrograms/mumol of O3, which increased to 150 micrograms/mumol in the midregion of a sigmoidal solubilization curve. Peptide fragments of the O3-solubilized elastin ranged in size from 5 to 20 kD. The conversion of insoluble elastin into soluble fragments by O3 was not due to the destruction of desmosine crosslinks. The effect of O3 on the proteolytic susceptibility of elastin was measured using insoluble elastin recovered from exposures that resulted in 5.3%, 12.8%, and 26.3% solubilization. Human neutrophil elastase (HNE) digested the remaining insoluble elastin samples 4.3, 6.0, and 9.8 times faster than unexposed elastin. In contrast, NO2-exposed elastin was no more susceptible to digestion by HNE. Ascorbate, EDTA, and uric acid reduced the proteolytic susceptibility of O3-exposed elastin, but mannitol afforded no protection. These findings indicate that the inhalation of O3 may contribute to lung disease by directly damaging elastin and by increasing its susceptibility to proteolysis, whereas NO2 probably damages lungs via alternative mechanisms.

Air Pollutants↗

PubMed1998

Remodeling of alveolar walls after elastase treatment of hamsters. Results of elastin and collagen mRNA in situ hybridization.

Treatment of hamster lungs with porcine pancreatic elastase (PPE) causes emphysema and a decrease in lung elastin content, which returns to control level by Day 30. To explore the mechanism of alveolar wall remodeling after elastolytic injury, we examined the expression of elastin and alpha1(I) collagen mRNAs by in situ hybridization at 1, 2, 3, 5, 7, and 30 d after intratracheal PPE. The lungs of control animals displayed weak signals for elastin and alpha1(I) collagen mRNA in pleura, large arteries, veins, and airways. There was little or no signal in respiratory air space walls. Increased expression of elastin and alpha1(I) collagen mRNA began by Day 1 after PPE and reached an asymptote by Day 3 that was maintained by elastin until Day 7; expression of alpha1(I) collagen mRNA waned earlier. Elastin and, to a lesser extent, alpha1(I) collagen mRNA were heavily expressed in pleura, blood vessels, and airways. Analysis of serial sections showed elastin message was minimal in the walls of respiratory air spaces and when present, at 3, 5, and 7 d, was primarily found at the free margins of alveolar septa. Collagen message was very sparse in respiratory air space walls. By 30 d, elastin mRNA expression was reduced but still above control levels and emphysema was widespread and severe. Rank score of elastin mRNA expression in individual subpleural air spaces showed a positive correlation with air space size. In conclusion, most expression of elastin and alpha1(I) collagen mRNA occurs in the pleura, airway, and vascular walls. In respiratory air space walls, expression of elastin mRNAs occurs in damaged tissue at free septal margins.

Animals↗

PubMed1989

Tumor cell interactions with elastin: implications for pulmonary metastasis.

Elastin surrounds microvessels in the pulmonary circulation and may pose a barrier to the extravasation of metastatic tumor cells. We find that lung-colonizing murine melanoma cells produce an enzymatic activity that degrades elastin. In addition, the elastin fragments liberated by enzymatic digestion of insoluble elastin stimulate tumor cell chemotaxis. Chemotactic activity is associated with other forms of soluble elastin, including alpha-elastin and tropoelastin. Val-Gly-Val-Ala-Pro-Gly, a synthetic peptide that is a repeat sequence in the elastin molecule, also displayed tumor cell chemotactic activity. The ability to degrade elastin and to migrate in response to soluble elastin peptides is not a property of all tumor cells, but it is most commonly found associated with metastatic tumor cells that colonize pulmonary tissue. We postulate that the ability to migrate in response to elastin fragments may facilitate tumor cell invasion of elastin-rich pulmonary tissue.

Animals↗

PubMed2001

Building Elastin. Incorporation of recombinant human tropoelastin into extracellular matrices using nonelastogenic rat-1 fibroblasts as a source for lysyl oxidase.

The purpose of this study was to assess the feasibility of crosslinking exogenously produced tropoelastin, the precursor of insoluble elastin, into existing elastin. Tritiated recombinant human tropoelastin (rhTE) was added to neonatal rat aorta smooth-muscle cell (NNRSMC) cultures. As much as 12% of the added rhTE was incorporated into the NNRSMC-derived insoluble elastin with the formation of the elastin crosslinks desmosine (DES) and isodesmosine (IDES) in a time-dependent fashion. The ratio of radioactivity found in DES and IDES crosslinks to that found in lysyl residues increased from 0.18 immediately after incubation with rhTE to 0.76 after 14 d. Crosslinking of rhTE into elastin and the accompanying formation of tritiated water was inhibited by beta-aminoproprionitrile, a potent inhibitor of lysyl oxidase, an enzyme critical for the post-translational processing of elastin and collagen. Acellular NNRSMC matrices were produced and replated with Rat-1 fibroblasts, cells that were found to express lysyl oxidase but not tropoelastin. At 14 d after incubation with rhTE, the ratio of DES and IDES radioactivity to that of lysine in the insoluble elastin was 0.38. We show for the first time that cells expressing lysyl oxidase, but not elastin, as well as elastogenic cells can incorporate rhTE into insoluble elastin with the formation of elastin crosslinks. This novel approach might be used to augment elastin repair in certain pathologic states.

Animals↗

PubMed1982

Marfan syndrome. Demonstration of abnormal elastin in aorta.

Aortae from three patients with classic presentation of Marfan syndrome, who died of vascular complications, were subjected to biochemical analyses of the connective tissue; for comparison, aortae from eight age-matched controls, without evidence of connective tissue abnormalities, were examined. Elastin was prepared from the aortae by two techniques. First, the tissues were extracted with 5 M guanidine-HCl, bacterial collagenase digestion and reduction with dithiothreitol (elastin I preparation). Secondly, this material was further purified by extraction with 0.1 M NaOH at 99 degrees C (elastin II preparation). Amino acid analyses of both elastin preparations indicated that the values for desmosine and isodesmosine were reduced in Marfan cases to approximately one-half of the control values. A corresponding increase in lysyl residues was noted in elastin II preparations. Also, the concentration of elastin per milligram dry weight of tissue was reduced in Marfan cases. The hydroxyproline content of elastin was increased in two cases with the Marfan syndrome. Recoveries indicated that the alkali treatment solubilized 46.2% of the elastin I preparations in Marfan aortae compared with 23.7% in controls. In contrast to elastin, the concentration and solubility of collagen were unchanged; the amino acid composition and the genetic types of insoluble collagen isolated by limited pepsin proteolysis were the same in both Marfan and control aortae. The results of our study demonstrate that the cross-linking of aortic elastin is reduced in the three patients with Marfan syndrome. Thus, a defect in elastin could explain the vascular fragility observed clinically in these patients.

Adult↗

PubMed1988

Repair of protease-damaged elastin in neonatal rat aortic smooth muscle cell cultures.

The objective of this study was to investigate the elastin repair process in the rat aortic smooth muscle cell culture after proteolytic injury. Although little studied in vivo, elastin repair is thought to occur through a sequential process involving enzymatic removal (debridement) of damaged fibers followed by synthesis of tropoelastin, its subsequent processing, and eventual incorporation into new insoluble elastin. A second repair mechanism of proteolytically damaged elastin in a culture system is reported here. Repair in this system relates directly to restoration of resistance to elastin solubilization by hot alkali. As expected, severe injuries were observed with porcine pancreatic elastase (PPE). Using PPE, only 6% of the elastin, relative to control, was resistant to hot alkali immediately after elastase treatment. 4 wk later, resistance to hot alkali had increased dramatically to a mean of 90%. Repair took longer after injury with 75 micrograms of PPE as compared with 50 micrograms of PPE. The limited elastic fiber proteolysis induced by either human neutrophil elastase or porcine trypsin was repaired in culture within 2 wk. Elastin that had been radiolabeled with [3H]lysine 4-5 wk before injury was converted from a hot NaOH-susceptible to a NaOH-resistant elastin fraction during recovery from PPE injury. At the same time, the frayed elastic fibers that were seen with the electron microscope immediately after PPE treatment were replaced by continuous bands of elastin that resembled those in control cultures. Restoration of NaOH resistance did not require a net increase in total cell layer elastin, suggesting that relatively little new tropoelastin incorporation into the cell layer was required for this type of repair. These results suggested a salvage repair mechanism for proteolytically damaged elastin.

Animals↗

PubMed1996

Modulation of elastin expression and cell proliferation in vascular smooth muscle cells in vitro.

Elastin expression in cultured vascular smooth muscle cell (VSMC) was found to be enhanced by potent inhibitors of VSMC proliferation including minoxidil, heparin and retinoic acid. By contrast, elastin expression was declined by potent stimulators of VSMC proliferation like epidermal growth factor, high K+, angiotension II and phorbol ester. To elucidate the relationship between elastin expression and cell proliferation, the elastin expression in the different cell growth states brought by cell-synchronizing culture or suspension culture, a culture system independent of potent modulators of VSMC proliferation. Elastin was found to be expressed maximally at G0 and minimally at G2/M phases, suggesting that cell growth state regulates elastin expression in VSMC culture. Synthetic elastin peptide VPGVG or its polymeric form (VPGVG)n enhanced VSMC proliferation, which resulted in the reduction of elastin expression. The results suggests that elastin fragment regulates VSMC proliferation. These correlation between elastin expression and cell growth state may play an essential role in elastin metabolism under the normal and diseased conditions.

Amino Acid Sequence↗

PubMed1989

Accumulation and regulation of elastin in the rat uterus.

The relative levels of elastin-specific mRNA were used as a measure of tropoelastin expression in uteri from pregnant Sprague-Dawley rats. The levels of elastin-specific mRNA were also correlated with values for net tropoelastin production and net deposition of mature, crosslinked elastin. The total content of uterine elastin increased throughout gestation, reaching maximal levels at Day 19 of gestation, which were three times those of nongravid tissue. Following involution, the elastin content decreased rapidly to near baseline values by 5 days postpartum. The content of soluble elastin, estimated using an enzyme-linked immunosorbent assay, paralleled in part the increase in elastin deposition and elastin mRNA levels. Uterine elastin metabolism appears to be unlike that in other elastic tissues, e.g., lung and large blood vessels. In most elastin containing tissues, the protein is synthesized during discrete developmental periods and is not readily degraded. However, uterine elastin is continuously expressed, and appears to be in a continual cycle of degradation and replacement.

Animals↗

PubMed1990

Elastin gene expression in elastotic human breast cancers and epithelial cell lines.

Elastosis is a prominent feature of the desmoplastic reaction in many invasive breast cancers. It is widely held that the elastic tissue is produced by fibroblastic cells of the breast stroma, but several studies have suggested that it derives from breast cancer epithelium. In studies directed to examining the mechanisms regulating desmoplasia in breast cancers, cell lines of human breast cancer derivation have been shown to synthesize immunoreactive tropoelastin in cell culture. Stromal fibroblasts, grown out from breast cancers, produced as much elastin as did nuchal ligament fibroblasts at similar passages. The human breast cancer cell lines, grown under similar conditions, produced elastin in culture at rates equivalent to 1.6-15% of those of the control fibroblastic cells. These included two estrogen receptor positive and one estrogen receptor negative cell types. Northern blot analysis of total RNA showed the presence, under high stringency conditions, of a 3.5-kilobase elastin mRNA band in both the fibroblastic cells and the cancer cell lines. In situ hybridization, with an elastin complementary RNA probe (prepared from a short segment of the translated region of human elastin mRNA), has been carried out on a selection of 21 invasive ductal breast cancers and 9 normal breast samples. It has been found that, while fibroblastic cells of the stroma and of the periductal region are responsible for elastin synthesis in most breast cancers, the malignant epithelium is a source of the elastin in the desmoplastic tissue of a significant proportion of such neoplasms. Vascular endothelium also expresses the elastin gene in some breast cancers. The elastotic elastin may have different cellular origins in different portions of a single ductal breast cancer. The results indicate that elastosis in breast cancers is very likely to be a complex process with multifactorial regulatory mechanisms. Subclassifying cancers according to the cellular source of the desmoplastic elastin, on the basis of in situ hybridization of elastin mRNA, may provide insights into the prognostic significance of elastosis in breast cancers.

Adult↗

PubMedDate not supplied

Dermal elastin and collagen in systemic sclerosis. Effect of D-penicillamine treatment.

Skin biopsies from 4 systemic sclerosis (SSc) patients, 6 SSc patients treated with D-penicillamine (from 8 to 60 months) and 4 normal subjects were analyzed by light and electron microscopy. By light microscopy, collagen bundles of SSc dermis were thicker and more compact than in age-matched controls; D-penicillamine treatment did not significantly modify their organization. On the contrary, a stereological analysis showed that the elastin volume density was higher in patients than in controls, and increased again after D-penicillamine treatment: moreover, the number of elastin fibers per unit area was significantly higher in the dermis of patients compared to controls, and became even higher after D-penicillamine treatment. The phenomena were evident in all strata of the dermis; however, the most significant increase of elastin in SSc patients compared to controls was in the superficial dermis, whereas after D-penicillamine treatment, all the strata of the dermis showed a significant increase in the percentage of elastin and in the number of elastin fibers per unit area compared to untreated patients and to controls. There were no relationships between elastin increase and time from the onset of SSc or time and dose of D-penicillamine treatment. At the ultrastructural level, collagen fibrils had rather heterogeneous diameters and formed more compact fibers, especially in the reticular and in the deep dermis of SSc patients compared to controls. After D-penicillamine, collagen fibril diameters in three of 5 patients examined were statistically wider and more heterogeneous than in controls and in untreated patients, whereas in the other 2 subjects both the mean diameter and the distribution of the class diameter were similar to both controls and untreated patients. This could suggest a specific individual reaction to the drug. Elastin fibers were smaller, more numerous and polymorphous in all patients compared to controls. After D-penicillamine, elastin fibers became even more numerous and smaller than in untreated patients. There was no correlation between the number and size of the elastin fibers and the time or dose of D-penicillamine. The internal organization of the elastin fibers was normal. These data indicate that the amount and distribution of collagen and elastin are altered in the dermis of SSc patients, and that D-penicillamine interferes with the deposition of both fibrous proteins in the dermal extracellular space.

Adult↗

PubMed1976

Demonstration of a precursor-product relationship between soluble and cross-linked elastin, and the biosynthesis of the desmosines in vitro.

Direct evidence showing that a soluble form of elastin is the precursor of cross-linked elastin was obtained from pulse-chase experiments using chick embryo aortas and by demonstrating the conversion of soluble elastin into cross-linked elastin in a cell-free system. Acetic acid extracts of embryonic chick aorta pulse-labeled with [14C]lysine contain two radioactive proteins of molecular weights 74,000 and 138,000 which have been identified previously as soluble elastin and the pro-alpha chain of collagen, respectively. In pulse-chase experiments, the radioactivity incorporated in the soluble elastin during the pulse with [14C]lysine disappeared during a 24-hour chase with [12C]lysine and 89% of that which disappeared was accounted for in the desmosines of alkali-insoluble elastin. The disappearance of the radioactivity from the soluble fraction and its appearance in the desmosines of elastin were inhibited by beta-aminopropionitrile, a specific inhibitor of the cross-linking enzyme lysyl oxidase. In addition in vitro experiments, it was shown that the radioactivity in the desmosines of elastin can arise from that present in an acid-soluble precursor protein. This precursor protein is soluble elastin, as demonstrated by the formation of desmosines when a homogeneous preparation of soluble elastin was incubated with purified lysyl oxidase.

Amino Acids↗

PubMed1999

Astrocytoma cell interaction with elastin substrates: implications for astrocytoma invasive potential.

Elastin has been identified within the meninges and the microvasculature of the normal human brain. However, the role that elastin plays in either facilitating astrocytoma cell attachment to these structures or modulating astrocytoma invasion has not been previously characterized. We have recently shown that astrocytoma cell lines and specimens produce tropoelastin, and express the 67 kDa elastin binding protein (EBP). In the present report, we have established that astrocytoma cells attach to elastin as a substrate in vitro. The U87 MG astrocytoma cell line demonstrated the greatest degree of adhesion. In addition, all astrocytoma cell lines examined were capable of penetrating and migrating through an intact elastin membrane, and of degrading tritiated-elastin, a process that could be prevented by the pre-incubation of astrocytoma cells with EDTA, but not with alpha1-antitrypsin. Astrocytoma cells were also capable of penetrating 1 mm sections of human brain tissue maintained as organotypic cultures. Interestingly, the invasive potential of cultured astrocytoma cells plated on organotypic cultures of human brain was significantly increased after exposure to elastin degradation products (kappa-elastin), which interact with astrocytoma cell surface EBP. Our data show that astrocytoma cells express a functional 67 kDa EBP, enabling them to potentially recognize and attach to elastin as a substrate. These data also suggest that this elastin receptor may be involved in processes which regulate regional astrocytoma invasion.

Astrocytoma↗

PubMed1995

Regulation of elastin synthesis in pathological states.

Elastin is rapidly deposited during late gestation in resilient tissues such as the arteries, lungs and skin owing to increased concentration of its mRNA. Pathological states can arise from congenital insufficiency or disorganization of elastin (cutis laxa). Other elastin deficiencies may be due to excess elastolysis or gene dosage effects. In the former, high turnover rates can be assessed by measurements of elastin degradation products in urine. Excess elastin accumulation by skin fibroblasts is characteristic of genetic diseases such as Buschke-Ollendorff syndrome, Hutchinson-Gilford progeria and keloid. Elastin expression is modulated by peptide growth factors, steroid hormones and phorbol esters, among which transforming growth factor beta (TGF-beta) is an especially potent up-regulator, acting largely through stabilization of mRNA. Recent evidence indicates cutis laxa fibroblasts that express little or no elastin have normal transcriptional activity but abnormal rates of elastin mRNA degradation. This defect is substantially reversed by TGF-beta through mRNA stabilization. Current studies explore the hypothesis that stability determinants lie within the 3' untranslated region of elastin mRNA. Post-transcriptional control of elastin expression appears to be a major regulatory mechanism.

Animals↗