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Molecular and Cellular Biology, November 1999, p. 7314-7326, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

An Open Reading Frame Element Mediates Posttranscriptional Regulation of Tropoelastin and Responsiveness to Transforming Growth Factor beta 1

Mancong Zhang,1,2 Richard A. Pierce,2,3 Hiroshi Wachi,2 Robert P. Mecham,2 and William C. Parks1,2,*

Departments of Pediatrics (Allergy and Pulmonary Division),1 Medicine (Dermatology Division),3 and Cell Biology and Physiology,2 Washington University School of Medicine, St. Louis, Missouri 63110

Received 24 June 1999/Returned for modification 27 July 1999/Accepted 2 August 1999

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 beta 1 (TGF-beta 1), 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-beta 1 was assessed by three distinct functional assays: (i) insertion of exon 30 into a heterologous gene conferred increased reporter activity after exposure to TGF-beta 1; (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-beta 1. 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.

* Corresponding author. Mailing address: Allergy and Pulmonary Division, Box 8116, St. Louis Children's Hospital, One Children's Place, St. Louis, MO 63110. Phone: (314) 454-7543. Fax: (314) 454-5372. E-mail: parks_w{at}kids.wustl.edu.

Molecular and Cellular Biology, November 1999, p. 7314-7326, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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