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Elastin is a resilient connective-tissue protein present in the extracellular matrix of most vertebrate tissues, but because of its unique elastomeric properties, this connective-tissue component is especially abundant in the interstitium of tissues that undergo repetitive physical deformations, such as the walls of alveoli and blood vessels (1). Elastic fibers are assembled extracellularly and are comprised of elastin and microfibrillar proteins. Elastin itself is a polymer of enzymatically crosslinked monomers of tropoelastin, the secreted, soluble precursor protein, and constitutes about 90% of the mass of elastic fibers. Microfibrils are complexes of large glycoproteins, such as fibrillin, that provide a scaffold for elastin polymerization.
The bulk of elastin expression is limited to a narrow window of development, and this defined temporal pattern provides a model for study of the molecular mechanisms controlling production of an age- and tissue-specific matrix protein. Elastin production begins around midgestation, peaks near birth and during early neonatal periods, drops sharply thereafter, and is nearly completely repressed by maturity. Because elastin is an extremely durable polymer and essentially does not turn over in healthy tissues, fiber function and tissue integrity are not compromised by the limited pattern of its production. Certain diseases and conditions, however, such as pulmonary hypertension, scleroderma, and fibrotic and granulomatous lung disease, are associated with a continued and excessive accumulation of elastin. In contrast, other conditions, such as emphysema and aneurysm, are characterized by destruction or a marked deficiency of elastin and, importantly, by an inability to repair or restore lost matrix. In these various conditions, excess or diminished elastin severely compromises the physiologic function, structure, and strength of the affected tissue. Because these conditions are not associated with mutation of the tropoelastin gene, their etiology is likely to involve an inability to properly regulate elastin production. Thus, to understand aberrant tropoelastin expression, we need to delineate the mechanisms that regulate normal elastin production.
Although transcriptional regulation controls the turning on and turning off of many developmentally regulated tissue-specific genes, tropoelastin production is governed by fundamentally distinct mechanisms acting at different stages of growth. In essentially all tissues and species, production of elastin correlates with the steady-state levels of its messenger RNA (mRNA). Our in vivo studies (2) have demonstrated that onset of lung elastin production is accompanied by induction of tropoelastin transcription, which is not at all surprising for an age-specific gene. In addition, in vitro findings support the idea that induction and stimulation of tropoelastin are controlled at the level of the gene. Insulin-like growth factor-1 (IGF-1) stimulates tropoelastin transcription, apparently by mediating the disruption of promoter-selective transcription factor-1 (Sp1) binding, which acts as a negative regulator of tropoelastin transcription (3). As shown by Liu and colleagues (4), retinoic acid stimulates tropoelastin transcription and protein production in neonatal lung fibroblasts, leading these authors to propose that this factor may participate in lung-cell differentiation.
In contrast, the repression of tropoelastin expression in vivo, as well as the suppression of its production in adult tissue, is controlled by a posttranscriptional mechanism mediating the rapid decay of tropoelastin mRNA. We found that transcription of tropoelastin pre-mRNA in adult lung continued at the same rate as found in neonatal lung long after steady-state mRNA levels had dropped and fiber assembly was complete (2). These findings indicate that a posttranscriptional mechanism affecting the processing or stability of tropoelastin mRNA regulates cessation of tropoelastin expression in vivo. In agreement with our findings, Kärähi (5) reported that glucocorticoids downregulate tropoelastin mRNA levels without affecting transcription, and McGowan and coworkers (6) demonstrated that the aprotinin-mediated decrease in tropoelastin expression in cell culture occurs solely through a reduction in mRNA half-life. Furthermore, Kelley and coworkers reported that marked downregulation of tropoelastin expression in ex vivo aorta is controlled solely by the accelerated decay of tropoelastin mRNA (7). Thus, destabilization of tropoelastin mRNA regulates the cessation of elastin production both in vivo and in various cell models.
Stimulation of tropoelastin expression by transforming
growth factor-
1 (TGF-1) represents an important and
potentially relevant exception to the rule that upregulation of elastin production is governed by the control of
gene transcription. As demonstrated by Kucich and coworkers (8), as well as in studies done with dermal fibroblasts (9, 10), TGF-1 potently stimulates tropoelastin expression in lung fibroblasts without affecting the rate of
gene transcription. Instead, TGF-1 mediates a marked stabilization of tropoelastin mRNA, leading to increased
steady-state transcript levels and enhanced protein production. Interestingly, Kucich and coworkers also demonstrated that stabilization of tropoelastin mRNA in lung
fibroblasts is mediated by a protein kinase C (PKC)-dependent pathway that is distinct from that involved in controlling transcript turnover in elastogenic cells of other tissues
(8). Because TGF-1 is thought to mediate fibrogenic responses in normal wound healing, this cytokine may be essential for reversing the posttranscriptional constraint on
tropoelastin expression and allowing renewed deposition of elastic fibers after tissue injury and damage to existing
matrix.
Proteins such as cytokines, iron-metabolism proteins, oncogenes, and cytoskeletal components, whose production is primarily regulated by a posttranscriptional mechanism, are expressed during physiologic transitions or for brief periods during developmental processes, and changes in the stability of their mRNAs provide a mechanism for rapidly governing protein synthesis and activity. In contrast, once the growth of elastic tissue is complete, new elastin production is not needed, and the posttranscriptional control of tropoelastin synthesis is therefore an unusual mechanism for controlling the expression of a stable structural protein. Although this is seemingly an inefficient mechanism, transcription is hardly a streamlined process. In addition to the need for splicing out of vast arrays of introns, most nuclear RNAs are not processed and transported to the cytosol. Furthermore, the 5'-flanking region of the tropoelastin gene resembles that of a typical housekeeping gene in that it contains GC-rich islands, has no consensus TATA box, and uses multiple start sites (11). In terms of evolutionary chronology, the elastin gene developed relatively recently, having evolved along with high-pressure circulatory systems and lungs. Thus, as compared with more ancient extracellular matrix proteins, such as the collagens and fibronectin, unique regulatory mechanisms may have evolved for the elastin gene.
The half-life of mRNA transcripts is modulated by specific RNA-binding proteins that interact with cis elements
in the 5' or 3' untranslated regions, the open-reading frame,
or the poly-A tail (12, 13). The heterogeneous localization
of regulatory elements among transcripts of different genes
indicates that mRNA decay is not mediated by a common
pathway. Tropoelastin mRNA does not contain any sequences that have been shown or suggested to mediate
degradation of other transcripts, such as AU-rich regions, and decay of tropoelastin mRNA may therefore be controlled by unique cis-acting sequences. Indeed, we have
found (M. Zhang and W. C. Parks, unpublished observations) that a conserved open-reading element specifically
binds a developmentally regulated cytosolic protein, suggesting that this trans factor directly or indirectly controls
age-specific decay of tropoelastin mRNA. Future studies will define the precise mechanisms regulating tropoelastin
transcript stability and how this process is affected in disease and by factors such as TGF-1.
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Address correspondence to: William C. Parks, Ph.D., Division of Dermatology, Barnes-Jewish Hospital North, 216 S. Kingshighway, St. Louis, MO 63110. E-mail: bparks{at}imgate.wustl.edu
(Received in original form February 12, 1997).
Acknowledgments: The author's research on elastin regulation is supported by Grant HL48762 from the National Institutes of Health and by a Genentech Scholar/American Lung Association Career Investigator Award.
Abbreviations
mRNA, messenger RNA;
Sp1, promoter-selective transcription
factor-1;
TGF-1, transforming growth factor-1.
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1. Parks, W. C., R. A. Pierce, K. A. Lee, and R. P. Mecham. 1993. Elastin. In Advances in Molecular and Cell Biology, Vol. 6. H. K. Kleinman, editor. JAI Press, Greenwich, CT. 133-182.
2.
Swee, M. H.,
W. C. Parks, and
R. A. Pierce.
1995.
Developmental regulation of elastin production. Expression of tropoelastin pre-mRNA persists after downregulation of steady-state mRNA levels.
J. Biol. Chem.
270:
14899-14906
3.
Jensen, D. E.,
C. B. Rich,
A. J. Terpstra,
S. R. Farmer, and
J. A. Foster.
1995.
Transcriptional regulation of the elastin gene by insulin-like growth
factor-I involves disruption of Sp1 binding. Evidence for the role of Rb in
mediating Sp1 binding in aortic smooth muscle cells.
J. Biol. Chem.
270:
6555-6563
4.
Liu, B.,
C. S. Harvey, and
S. E. McGowan.
1993.
Retinoic acid increases elastin in neonatal rat lung fibroblast cultures.
Am. J. Physiol.
265:
L430-L437
5. Kähäri, V. M.. 1994. Dexamethasone suppresses elastin gene expression in human skin fibroblasts in culture. Biochem. Biophys. Res. Commun. 201: 1189-1196 [Medline].
6.
McGowan, S. E.,
R. Liu,
C. S. Harvey, and
E. C. Jaeckel.
1996.
Serine proteinase inhibitors influence the stability of tropoelastin mRNA in neonatal
rat lung fibroblast cultures.
Am. J. Physiol.
270:
L376-L385
7.
Johnson, D. J.,
P. Robson,
Y. Hew, and
F. W. Keeley.
1995.
Decreased elastin synthesis in normal development and in long-term aortic organ and cell
cultures is related to rapid and selective destabilization of mRNA for elastin.
Circ. Res.
77:
1107-1113
8.
Kucich, U.,
J. C. Rosenbloom,
W. R. Abrams,
M. M. Bashir, and
J. Rosenbloom.
1997.
Stabilization of elastin mRNA by TGF-: initial characterization of signaling pathway.
Am. J. Respir. Cell Mol. Biol.
17:
10-16
9.
Kähäri, V.-M.,
D. R. Olsen,
R. W. Rhudy,
P. A. Carillo,
Y. Q. Chen, and
J. Uitto.
1992.
Transforming growth factor- upregulates elastin gene expression in human skin fibroblast: evidence for posttranscriptional modulation.
Lab. Invest.
66:
580-588
[Medline].
10. Zhang, M. C., M. Giro, D. Quaglino Jr., and J. M. Davidson. 1995. Transforming growth factor-beta reverses a posttranscriptional defect in elastin synthesis in a cutis laxa skin fibroblast strain. J. Clin. Invest. 95: 986-994 .
11.
Bashir, M. M.,
A. Indik,
H. Yeh,
N. Ornstein-Goldstein,
J. C. Rosenbloom,
W. Abrams,
M. Fazio,
J. Uitto, and
J. Rosenbloom.
1989.
Characterization of the complete human elastin gene. Delineation of unusual features in the
5'-flanking region.
J. Biol. Chem.
264:
8887-8891
12. Sachs, A. B.. 1993. Messenger RNA degradation in eukaryotes. Cell 74: 413-421 [Medline].
13. Ross, J.. 1996. Control of messenger RNA stability in higher eukaryotes. Trends Gen. 12: 171-175 [Medline].
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