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Plasminogen is one of the key elements in the fibrinolytic process. Like most of the gene products that participate in such reactions and which interact with plasminogen, the site of its synthesis is mainly confined to the hepatocyte. Plasminogen RNA has additionally been detected in kidney and very low amounts also in testes. Deletional analysis has indicated that two 5' sequences located within 2.5 kb of the first ATG are responsible for the transcriptional activation and the tissue specificity of the expression of the gene. By DNase protection and gel mobility shift assays with HepG2 nuclear extracts, the two sequences were localized and found to be the recognition sites for the widely known hepatocyte nuclear factor 1 (HNF-1) a trans-acting factor, and a nuclear factor like activator protein 3 (AP-3). The first one lies in a rather unusual position, i.e. within the 5'-untranslated region. The latter is located further upstream in a region between -2200 and -2100 from the plasminogen mRNA cap site. Moreover, sitedirected mutagenesis coupled by functional experiments in HepG2 cells has demonstrated a synergism between these two positively acting elements in controlling the transcription of the human plasminogen gene.Keywords: plasminogen; apoprotein(a) ; gene cluster; promoter; trans-acting factors.Plasminogen is a zymogen synthesized in the liver which is involved in the final step of fibrinolysis. During this process plasminogen is converted to plasmin following the action of a number of activators, including tissue plasminogen activator and urokinase [l]. The one-chain proenzyme is converted to a twochain active plasmin molecule by cleavage of a specific internal peptide bond between Arg560 and Val562 [2]. The carboxy portion of the protein contains the serine protease function of the molecule which shows a remarkable degree of homology with the serine proteases involved in blood coagulation and other physiological processes [3]. On the other hand, in the aminoterminal region there are five tandem repeats called kringles (1 -5) and a leader sequence [3, 41. Kringle modules, which are also present in several members of the serine protease superfamily, are protein binding domains important for the specificity, function and regulation of these proteins [3].An impressive sequence similarity with plasminogen, both at the protein and DNA levels, has been discovered with the cloning of the cDNA coding for apoprotein(a) [5]. Apoprotein(a), like plasminogen, comprises a 5' signal peptide, multiple repeats of a kringle-IV-like motif, followed by a single kringle-V-like domain and a protease module [5J. Recent YAC cloning has revealed that the genes coding for plasminogen and apolipoprotein(a) are separated by 40 kb of genomic DNA on the telomeric region of chromosome 6 (6q26) and are organized in a head-to-head configuration [6-91. Moreover, the same YAC cloning approach has also uncovered the presence of two otherCorrespondence to

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