PubMed1991
Recent isolation and characterization of cDNAs encompassing the full length of chicken, cow, and human elastin mRNA have led to the elucidation of the primary structure of the respective tropoelastins. Comparison of the tropoelastin from the different species has revealed that large segments of the sequence are conserved, but considerable variation also exists, ranging in extent from relatively small alterations, such as conservative amino acid substitutions, to large-scale deletions and insertions. Several distinct approaches have yielded compelling evidence of a single elastin gene per haploid genome. Analysis of the bovine and human elastin genes revealed that functionally distinct hydrophobic and cross-link domains of the protein are encoded in separate exons which alternate in the genes. The human gene contains 34 exons, the intron/exon ratio is unusually large (20:1), and the introns contain large amounts of repetitive sequences that may predispose to genetic instability. Comparison of the cDNA and genomic sequences has demonstrated that the primary transcript of both species is subject to considerable alternative splicing, which can account for the presence of multiple tropoelastin isoforms. It is likely that the conformation of elastin is, at least in part, that of a random coil, and therefore it might be expected that the stringency for conservation of the amino acid sequence would be less than that for other proteins with unique conformations. This suggests that functional elastin molecules that vary in their sequence and fitness may exist in the human population and be compatible with a normal life. Potentially though, these variations could have profound consequences on the properties of vital tissues found in the cardiovascular and pulmonary systems over the lifetime of the individual. Consequently, analysis of the structure of the elastin gene and its variation in what is regarded as the normal human population, rather than in those individuals with clearly heritable diseases, assumes greater importance. The 5'-flanking region of the gene is G + C rich and contains several SP-1 and AP2 binding sites, as well as putative glucocorticoid, cAMP, and TPA responsive elements, but no consensus TATA box or functional CAAT box. Primer extension and S1 mapping of the elastin mRNA indicated that transcription was initiated at multiple sites. Transfection experiments using promoter elements/reporter gene constructs demonstrated that the basic promoter element was found within region -128 to -1. In addition, three distinct up-regulatory and two down-regulatory regions were delineated. Taken together, these findings suggest that the regulation of elastin gene expression is complex and takes place at several levels.