IntroductionThe ␣1-antitrypsin (AT) is the most abundant circulating protease inhibitor in plasma (1-2 mg/ml) and a prototypical member of the serpin (serine protease inhibitor) superfamily [1,2]. It is primarily synthesized by the hepatocyte and enters the lung by passive diffusion to protect the alveolar matrix from proteolysis, particularly by neutrophil elastase [1][2][3][4][5][6]. The secondary structure of active AT is composed of three ␤-sheets (A, B and C), nine ␣-helices (A-I), and a reactive centre loop (RCL) which tightly entraps neutrophil elastase and other target proteases [6][7][8] [10][11][12]. The accumulation of Z-AT polymers within the hepatocyte causes liver cirrhosis and the resultant plasma deficiency can give rise to early-onset emphysema [13][14][15][16][17]. Polymerization of other serpin variants such as those of antithrombin III, ␣1-antichymotrypsin, C1-inhibitor and neuroserpin have also been described and related to thrombosis, emphysema, angioedema and dementia, respectively [18, 19]. [18,[20][21][22][23][24] Given that protein aggregation is the origin for the pathogenesis of the liver and lung diseases associated with Z-AT, the crux of the matter is to inhibit the oligomerization process and thus prevent the intracellular accumulation of Z-AT polymers. Previous studies have shown that 11-to 13-mer synthetic peptides with homology to the RCL could anneal to the A-sheet of AT

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Approximately one quarter of the identified human serpin genes are cancer-related and clustered mainly at two distinct loci: 6p25 and 18q21. We have studied a novel serpin gene cluster at 3q26 containing at least two recently identified members: the pancreas-specific protease inhibitor, pancpin (PI14), and the brain-associated protease inhibitor, neuroserpin (PI12). In this, unlike a previous study, both PI14 and PI12 at 3q26 were found to consist of 9 exons and 8 introns and to share a perfectly conserved gene organization whose pattern is very different from that of the ov-serpin family. This distinct pattern appears identical in the genomic structures of human plasminogen activator inhibitor-1 (PAI1) at 7q21 and protease nexin 1 (PI7) at 2q33-35, confirming that these four genes in three different chromosomes form a discrete subset within the serpin superfamily. As in the other three members whose gene expression is altered during tumorigenesis, PI12 expression was found to be down-regulated in tumor brain tissues and in two brain cancer cell lines: U-87 MG and H4. By screening genomic libraries, we isolated two overlapping clones showing that the marker SGC32223 (centromere) is located within intron F of PI12 and the marker WI-10077 (telomere) is located downstream of the 3'-flanking region of PI14. This finding indicates that the distance between human PI14 and PI12 is approximately 100 kb, and hence we speculate that other tissue-specific cancer-related serpin genes are likely to reside within this 3q26.1 cluster region.

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