Disease relevance of KLK1  

• Linkage was shown between the myotonic dystrophy locus (DM) and a highly polymorphic AC repeat marker within the kallikrein (KLK1) locus (Z = 3.00, theta = 0.0) [1].
• The observed genetic association suggests an etiologic effect of the KLK1 promoter on hypertension and/or hypertension associated ESRD [2].
• The -130 G12 allele in the KLK1 promoter was associated with lower transcriptional activity and hypertensive end-stage renal disease (ESRD) in blacks [3].
• Both kallikrein immunoreactivity and KLK1 mRNA have been detected in the rat anterior pituitary and oestrogen induced prolactinomas [4].
• The human tissue kallikreins (KLKs 1-3) and a novel KLK1 mRNA transcript are expressed in a renal cell carcinoma cDNA library [5].

Psychiatry related information on KLK1

• This indicates that normal KLK1 genes, expressed as variants in this RFLP, do not participate in the determination of the limits within which life-style factors may cause blood pressure (BP) changes [6].

High impact information on KLK1

• The importance of the tissue kallikrein system depends upon secretion of the active form of the requisite enzyme in the presence of a source of kininogen [7].
• In this review, we summarize the recently accumulated knowledge on the human tissue kallikrein gene family, including gene and protein structure, predicted enzymatic activities, tissue expression, hormonal regulation, and alternative splicing [8].
• As inactivation of the TK gene in the mouse induces endothelial dysfunction, we investigated the vascular, hormonal, and renal phenotypes of carriers of the 53H allele [9].
• The partial genetic deficiency in TK activity is associated with an inward remodeling of the brachial artery, which is not adapted to a chronic increase in wall shear stress, indicating a new form of arterial dysfunction affecting 5-7% of white people [9].
• Direct gene delivery of human tissue kallikrein reduces blood pressure in spontaneously hypertensive rats [10].

Chemical compound and disease context of KLK1

• Linkage between KLK1 and the highly polymorphic AC repeat marker within the apolipoprotein C2 (APOC2) locus, which had been established in normal families, was confirmed in myotonic dystrophy families (Z = 4.37, theta = 0.11) [1].
• Moreover, tissue kallikrein was found in malignant human breast tissue and bradykinin (BK) stimulates the proliferation of immortalised breast cancer cells [11].
• We investigated the effect of enhanced kallikrein levels on kidney remodeling of DOCA-salt hypertensive rats by systemic delivery of adenovirus containing human tissue kallikrein gene [12].
• Human and rat prolactinomas contain markedly increased amounts of tissue kallikrein; this is comparatively reduced if patients are pretreated with the dopamine agonist, bromocriptine, before surgery [13].
• Infection of isolated rat aortic segments with adenovirus containing the human tissue kallikrein gene resulted in a time-dependent secretion of recombinant human tissue kallikrein, and significant increases in nitric oxide (NOx) and guanosine 3',5'-cyclic monophosphate (cGMP) levels post gene transfer [14].

Biological context of KLK1

• This new gene maps to chromosome 19q13.4 and is located between the KLK1 and KLK3 genes [15].
• METHODS: A total of 15 haplotypes were identified in the KLK1 promoter region through detailed DNA sequence analysis [2].
• In KLK1 promoter, the -130 GN length polymorphism and multiple single base substitutions were analyzed by electrophoresis of fluoresced PCR products in sequencing gels, single strand conformation polymorphism (SSCP), allele-specific PCR, and DNA sequencing [3].
• We also determined the nucleotide sequence of KLK15 and the intergenic region between this gene and KLK1 in the cotton-top tamarin [16].
• Human glandular Kallikrein genes: genetic and physical mapping of the KLK1 locus using a highly polymorphic microsatellite PCR marker [17].

Anatomical context of KLK1

• The KLK1 locus was also localized physically using somatic cell hybrid DNA templates for polymerase chain reaction analysis [17].
• Protein expression was confirmed by precipitation of KLK1 from lysates of endothelial cells pre-labeled with [35S]-cysteine/methionine [18].
• KLK1, 4, 5, 6, 7, 8, 10, 11, 13 and 14 are expressed in both cerebral cortex and hippocampus [19].
• In order to provide further evidence for a local kallikrein-kinin system in this tissue, we wished to determine if the gene encoding kallikrein (KLK1) was expressed in the human uterus and determine the pattern of its expression across the menstrual cycle [20].
• KLK1 expression was similar across the estrous cycle and early pregnancy, and localized to the endometrial luminal (L) and glandular (G) epithelium [21].

Associations of KLK1 with chemical compounds

• Expression and Functional Characterization of the Cancer-related Serine Protease, Human Tissue Kallikrein 14 [22].
• Specificity of human tissue kallikrein towards substrates containing Phe-Phe pair of amino acids [23].
• Internally quenched fluorogenic peptides were synthesized with the general structure Abz-peptidyl-EDDnp [Abz, o-aminobenzoic acid; EDDnp, N-(2, 4-dinitrophenyl)ethylenediamine], based on the natural reactive-centre loop sequence of kallistatin from P9 to P'13, and the kinetic parameters of their hydrolysis by hK1 were determined [23].
• Glandular kallikrein is about 500-fold less active than is PK or tissue kallikrein, but it may play a physiologically important role in bradykinin release in seminal fluid [24].
• Heparin blocks kallistatin's complex formation with tissue kallikrein and abolishes its inhibitory effect on tissue kallikrein's activity [25].

Physical interactions of KLK1

• Kallistatin is a newly identified serine proteinase inhibitor (serpin) which binds to tissue kallikrein and inhibits its enzymatic activity in vitro [26].
• Seminal plasma collected in the absence of extrinsic inhibitors contained 1.8 +/- 0.6 nM tKK:PCI complex and 4.7 +/- 2.8 nM immunoreactive tKK (mean +/- SD, n = 10), which indicates that about 28% of the total tKK immunoreactivity is forming complexes with PCI [27].

Enzymatic interactions of KLK1

• Tissue kallikrein is a serine proteinase which is capable of cleaving kininogen substrate to release the vasoactive kinin peptide [28].
• We also observed that human tissue kallikrein hydrolysed growth hormone-releasing hormone at the Arg11-Lys12 bond, although this peptide contains in its structure a pair of leucines (Leu22-Leu23), in contrast with the Phe-Phe pair in somatostatin [29].

Co-localisations of KLK1

• Immunoreactive tissue kallikrein was co-localized with prolactin in all the eleven prolactin-secreting adenomas of the human anterior pituitary gland examined in this study [30].

Regulatory relationships of KLK1

• The results show that kallistatin is a new member of the serpin superfamily that inhibits human tissue kallikrein [25].
• It has not been studied in conditions with predominantly neutrophilic bronchial secretions, although animal data indicate that neutrophil elastase may stimulate TK activity [31].
• Protein C inhibitor (PCI) inhibits tissue kallikrein by forming stable 1:1 complexes (k1 = 2.3 x 10(4)M-1s-1) [32].
• These diabetic cardiomyopathy-associated alterations were significantly attenuated (P<0.05) in diabetic transgenic rats expressing the human kallikrein 1 (hKLK1) gene with STZ-induced diabetes [33].

Other interactions of KLK1

• The third human tissue kallikrein to be identified, hK2, could be an alternate or complementary marker to kallikrein hK3 (prostate-specific antigen) for prostate diseases [34].
• Human tissue kallikrein 14 (KLK14) is a novel extracellular serine protease [22].
• Two members of the human tissue kallikrein (KLK) family of (chymo)tryptic-like serine proteases, KLK5 and KLK7, are implicated in desquamation by digestion of (corneo)desmosomes and inhibition by desquamation-related serine protease inhibitors (SPIs) [35].
• Addition of Vn reduced this complex formation, whereas, in contrast, complexes of PCI and TK appeared [36].
• However, the frequency distribution of KLK1 promoter among VUR patients with or without CRI (A, 50.0% and 67.5%; B, 17.9% and 8.3%; H, 14.3% and 18.3%; K, 17.9% and 5.8%, respectively) was statistically different (P = 0.008) [3].

Analytical, diagnostic and therapeutic context of KLK1

• The expression of KLK1 and KLK3 was further confirmed by sequence analysis of three different endometrial PCR products [37].
• MEASUREMENTS: Pituitary total RNA was subjected to both Northern blot analysis, with KLK1 and KLK2 cDNA probes, and KLK-specific reverse transcriptase -- polymerase chain reaction (RT-PCR) [4].
• Partial purification of tissue kallikrein from total endothelial cell extracts resulted in a protein triplet of about 50 kDa in Western blots using specific anti-KLK1 antibodies [18].
• Tissue kallikrein levels are reduced in humans and in animal models with hypertension, cardiovascular and renal diseases [38].
• Western blotting of HUVEC medium using anti-human tissue kallikrein antibodies demonstrated the release of tissue kallikrein from HUVEC, and the reverse transcription-polymerase chain reaction (RT-PCR) followed by Southern blotting revealed the expression of tissue kallikrein mRNA in HUVEC [39].

References