Human KLK1 blocking peptide

Recently, a genome- wide screen has shown a major quantitative trait locus ( QTL) for a stroke- associated phenotype on rat chromosome 1 ( RNO1) independent of QTL for blood pressure ( BP) in the stroke- prone spontaneously hypertensive rat ( SHRSP) of a Heidelberg colony. However, it remains to be elucidated whether these observations reflect the existence of different genes predisposing to each of the disorders. To address this issue, we performed comprehensive approaches in a Japanese colony, Izm, as follows. First, we undertook genome- wide searches in F-1( SHRSP/ Izm x WKY/ Izm) x SHRSP/ Izm back- cross ( n = 63) to pursue a causal relation between hypertension and stroke. Although the strongest linkage to BP ( LOD score of 3.4) was identified on RNO1, its relevance to stroke was not supported in the F-1 back- cross studied. Second, we also investigated linkage to BP in F-2 progeny ( n = 175) involving the stroke- resistant ( or normal) spontaneously hypertensive rat ( SHR). In F-2 studies of SHR/ Izm, this locus did not appear to constitute a principal BP QTL. Third, we constructed congenic animals with detailed phenotype characterization. Transfer of a chromosomal fragment between markers Klk1 and D1Rat116 from WKY/ Izm onto the SHRSP/ Izm background lowered systolic BP by 20 to 80 mm Hg, prevented development of apparent stroke, and exaggerated impaired glucose tolerance. In conclusion, we have successfully isolated an RNO1 region affecting BP, stroke, and glucose tolerance in SHRSP/ Izm- derived congenic rats. The size of the introgressed region is large, but our novel congenic strain should help delineate complex, genetic impairments underlying BP and associated vascular disease phenotypes.

Background: All human kallikrein (KLK) genes have at least one splice variant, some of which possess clinical utility in cancer diagnotics/prognostics. Given that introns <100 bp in length are retained in 95% of human genes and that splice variants of KLK3 and KLK4 retain intron III, we hypothesized that other proteins in this family, with a small intron III, may also retain it. Methods: Variant-specific reverse transcription-PCRs (RT-PCRs) for KLK1, KLK2, KLK5, and KLK15 were used to identify and clone the full coding sequence of intron Ill-containing splice variants. In addition, variant-specific RT-PCRs for the cloned KLK3 and KLK4 variants as well as for the "classical" forms of the six genes were used to determine their expression profiles in healthy tissues, their regulation by steroids, and their differential expression in prostate cancer. Results: KLK1, KLK2, KLK3, KLK4, KLK5. and KLK15 showed a common type of splice variant in which intron III is retained. Expression profiling of these splice variants revealed expression profiles similar to those of the classical mRNA forms, although the pattern of hormonal regulation was different. The KLK15 splice variant was tip-regulated in 8 of 12 cancerous prostate tissues. All encoded variant proteins were predicted to be truncated and catalytically inactive because of a lack of the serine residue of the catalytic triad. Conclusions: The first six centromeric members of the KLK gene family have splice variants that retain intron III. Some variants show tissue-specific expression. The KLK15 splice variant appears to be a candidate biomarker for prostate cancer. (C) 2005 American Association for Clinical Chemistry.