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Posttranscriptional Regulation of Lung Elastin Expression Involves Binding of a Developmentally Regulated Cytosolic Protein to an Open-Reading Frame cis-Element in the Messenger RNA^*

^* From the Departments of Pediatrics and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO.

Correspondence to: William C. Parks, PhD, Washington University School of Medicine, Department of Pediatrics, One Children's Pl, St. Louis, MO 63110

The bulk of lung elastin production occurs during late fetal and neonatal development, and by maturity, assembly of elastic fibers is complete, and synthesis of tropoelastin, the soluble precursor, has ceased. Certain conditions, however, such as fibrosis and pulmonary hypertension, are associated with abnormal production of elastin. We reported that the cessation of lung elastin production is controlled strictly by a posttranscriptional mechanism. Although tropoelastin premessenger RNA (mRNA) is transcribed at the same rate in neonatal and adult tissue, the fully processed transcript does not accumulate in adult lung. We have since demonstrated that the rate of tropoelastin pre-mRNA processing is equal in neonatal and adult lung fibroblasts but that the cytosolic mRNA is rapidly degraded in adult cells. These findings suggest that a cytosolic trans-factor interacts with a specific cis-element in tropoelastin mRNA and that this interaction mediates the accelerated decay of the transcript in adult cells. Indeed, using a modified RNase-protection assay, we found that only RNA probes containing sequences coded by exon 30 and incubated with cytosolic extract from adult lung fibroblasts were protected from degradation by T1 RNase. Specific products were competed with excess cold exon 30 RNA but not by nonspecific cold RNA. Phenol extraction revealed that the protected mRNA fragment was about 9 to 11 nucleotides. The level of binding activity was much greater in cytosolic extracts of adults cells than of neonatal fibroblasts and was inhibited by treatment with transforming growth factor-beta 1, which is known to stabilize tropoelastin mRNA. Ultraviolet crosslinking demonstrated that the binding protein is about 52 kd. Functional assays in which exon 30 was inserted in a heterologous expression construct or was used as a competitor in an in vitro degradation assay verified the role of this region in regulating instability of tropoelastin mRNA. Thus, we have revealed a unique mechanism that controls production of a developmentally regulated structural protein and that may be inoperative during the aberrant accumulation of elastin in disease.

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This Article Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, M. Articles by Parks, W. C. Search for Related Content PubMed PubMed Citation Articles by Zhang, M. Articles by Parks, W. C.