Potential basis for regulation of the coordinately expressed fibrinogen genes: homology in the 5' flanking regions.

Abstract

The 3 chains of fibrinogen are encoded by 3 separate genes whose transcription is coordinately regulated. The breakdown of fibrinogen during the acute-phase reaction leads to a simultaneous increase in .alpha.-, .beta.- and .gamma.-fibrinogen mRNA in the liver. In a search for the basis of this coordinate increase in transcription, the sequences of the regions surrounding the points of transcriptional initiation of the 3 rat fibrinogen genes, 1490 nucleotides upstream and 730 nucleotides downstream were determined. Two unique regions of homology were found. One region consists of 15 nucleotides that have a common 6-nucleotide core lying between -116 and -160; the other is .apprxeq. 100 nucleotides long and is in the -165 to -472 region. In this region, the .beta.- and .gamma.-fibrinogen genes are .apprxeq. 65% homologous. .alpha.-Fibrinogen has somewhat less homology with both .beta.- and .gamma.-fibrinogen. The .beta.-fibrinogen gene has 22 nucleotides at position -480 that are homologus to sequences that were noted to occur in glucocorticosteroid-regulated genes in a similar position. These areas of conserved sequences play a role in the regulation of the transcription of fibrinogen. The fibrinogen chains are synthesized as precursor peptides, anid the amino-terminal portion, the so-called signal peptide, is remove during the translocation of the peptide chain across the endoplasmic reticulum. Those sequences that encode the signal peptides were determined. Homology in the amino acid sequence between the rat and human signal peptides varies between 52% for .alpha.-fibrinogen and 66% for .beta.-fibrinogen. There was probably strong selective pressure on this portion of these genes.