Disease relevance of KLK3

• For example, prostate-specific antigen (or KLK3) is a secreted protein that is widely used as a diagnostic marker for prostate cancer [1].
• Short sequence repeat polymorphisms for the human plasma kallikrein gene (KLKB1; previously known as KLK3) on chromosome 4 were associated with ESRD in an African American study population [2].
• RT-PCR for PSA, hK2-L, and hK2-U were positive in 24, 25, and 26%, respectively, of prostatectomy patients; 88, 71, and 86%, respectively, of patients with metastases to bones; 7, 14, and 36%, respectively, of healthy men [3].
• Recombinant pro-PSA was expressed in Escherichia coli, isolated from inclusion bodies, refolded, and purified [4].
• Prostate-specific antigen (PSA) is a well-established tumor marker of prostatic adenocarcinoma [5].
• Taken together with the finding that the G-158A polymorphism is associated with an increased risk of prostate cancer in Australian men, our functional data suggest that the presence of the A allele in AREI may, in part, account for the altered PSA regulation seen in prostate cancer [6].
• In a prospective cohort of men enrolled into expectant management for prostate cancer, serum and tissue levels of proPSA at diagnosis are associated with need for subsequent treatment [7].

Psychiatry related information on KLK3

• However, the effect of physical activity on the PSA concentration in serum is controversial [8].
• PRACTICE IMPLICATIONS: This brief pDA could serve as an acceptable and low cost adjunct to counselling by the General Practitioner (GP), and should promote informed decision making regarding the PSA test [9].
• A sensitive sandwich enzyme immunoassay for gamma-seminoprotein and its application to sex discrimination of blood and bloodstains [10].
• There was no increase in the HADS scores, or reduction in the SF-12 mental health component summary score, on attendance at the biopsy clinic after receiving an 'abnormal' PSA result [11].
• As the risk for such progression is higher in patients with larger glands or higher serum PSA values at baseline, it is in those patients that finasteride induces an even greater risk reduction, making it a cost-effective treatment choice for patients with LUTS associated with prostatic enlargement [12].

High impact information on KLK3

• Reporting in this issue of Cell, Kasper and colleagues (Mazmanian et al., 2005) reveal that a bacterial polysaccharide, PSA, produced by the commensal bacterium Bacteroides fragilis directs development of the immune system of the mouse host [13].
• We conclude that PSA is more sensitive than PAP in the detection of prostatic cancer and will probably be more useful in monitoring responses and recurrence after therapy [14].
• PSA was increased in 86 percent and PAP in 14 percent of the patients with benign prostatic hyperplasia [14].
• This test detects as little as 3 ng of the p30 antigen per milliliter in various body fluids [15].
• The p30 antigen was detectable in vaginal fluid for a mean period of 27 hours after coitus, as compared with 14 hours for prostatic acid phosphatase [15].

Chemical compound and disease context of KLK3

• Moreover, selenomethionine (SM), a prostate cancer treatment adjuvant, shows an inhibitory effect on LNCaP cell growth, yet has no effect on the AR/PSA pathway [16].
• Here we demonstrate that alpha-tocopheryl succinate (VES) can suppress the expression of prostate-specific antigen (PSA), a marker for the progression of prostate cancer [16].
• CONCLUSION: Osteoblasts secrete factors, such as IL-6, that cause androgen-independent induction of PSA gene expression and proliferation of prostate cancer cells by a mechanism that partially relies on the AR [17].
• Human glandular kallikrein 2 (hK2), another serine protease closely related to PSA, is also gaining ground as a promising diagnostic tool in prostate cancer [5].
• Measurement of its antineoplastic activity in prostate cancer clinical trials may be complicated by effects of calcitriol on prostate-specific antigen (PSA) production [18].

Biological context of KLK3

• KLK15 is newly discovered kallikrein gene that is located adjacent to KLK3 on chromosome 19q13 [19].
• The human kallikrein gene cluster, located in the chromosome band 19q13, contains several tissue-specific serine protease genes including the prostate-specific KLK2, KLK3 and prostase genes [20].
• Fifteen kallikrein genes were located in the chimpanzee (Pan troglodytes) genome, while only 14 were identified in the canine (Canis familiaris) genome as no orthologue to human KLK3 was found [21].
• Our study suggests that in addition to the four AREs identified in the PSA enhancer core, another regulatory element (GAGATA), which is located at the region designated PSA3.1, also contributes to transcriptional regulation by androgens [22].
• The main activity of this 5.8-kb PSA promoter resides in a 455-bp enhancer core region located about 4 kb upstream of the TATA box [22].

Anatomical context of KLK3

• The significance of the novel expression of KLK2 and KLK3 (PSA), previously thought to be prostate-specific genes, in the endometrium is unclear [23].
• In situ hybridization revealed that, in prostate, KLK14 is expressed by both benign and malignant glandular epithelial cells, thus exhibiting an expression pattern similar to that of two other prostatic kallikreins, KLK2 and KLK3, which encode K2 and prostate-specific antigen, respectively [24].
• Prostase shares 35% amino acid identity with prostate-specific antigen (PSA) and 78% identity with the porcine enamel matrix serine proteinase 1, an enzyme involved in enamel matrix degradation and with a putative role in the disruption of intercellular junctions [25].
• Human glandular kallikrein (hK2) protein, like prostate-specific antigen (PSA), is produced mainly in prostatic epithelium [26].
• The recombinant pro-PSA was also activated by recombinant human glandular kallikrein, another prostate-specific serine protease, as well as by a partially purified protease(s) from seminal plasma [4].

Associations of KLK3 with chemical compounds

• Together, our data indicate that VES may suppress androgen/AR-mediated cell growth and PSA expression by inhibiting AR expression at both the transcription and translation levels [16].
• Moreover, DIM inhibited endogenous PSA transcription and reduced intracellular and secreted PSA protein levels induced by DHT in LNCaP cells [27].
• A binding motif is present in the PSA and hGK-1 promoters, closely resembling the consensus sequence for steroid-responsive elements [28].
• Treatment of cells with cycloheximide demonstrates that, while PSA/hGK-1 basal transcription strictly depends on continuous protein synthesis, transcriptional induction by androgen does not [28].
• A weak correlation was observed between urinary PSA and serum 3 alpha-androstanediol glucuronide (r(s) = 0.42, P = 0.03) as well as between urinary PSA and serum testosterone (r(s) = 0.40, P = 0.04) [5].

Physical interactions of KLK3

• Contrary to earlier assumptions, nicked PSA can bind to A2M rendering it inaccessible to antibodies [29].
• It has been hypothesized that the AR (androgen receptor) gene binds the two PSA (prostate-specific antigen) alleles with differing affinities and may differentially influence prostate cancer risk [30].
• PSA complexed to alpha 1-antichymotrypsin (ACT) is the predominant molecular form of serum PSA, although complex formation is slow between the purified proteins in vitro [31].
• A few per cent of PSA in semen is complexed to the protein C inhibitor [32].
• Prostate specific antigen (PSA) is an insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) protease found in seminal plasma and produced by prostatic epithelial cells (PC-E) in vivo [33].

Enzymatic interactions of KLK3

• Autoradiographs measuring IGFBP-3 protease activity demonstrated that purified PSA cleaved IGFBP-3, yielding a cleavage pattern identical to that of seminal plasma [34].
• PCI was found to inhibit the PSA-catalyzed degradation of insoluble coagula Sg I + II by forming a PSA-PCI complex [35].
• Our data show that PSA proteolytically cleaves PTHrP (1-34) after either residue 22 or 23, generating three peptide fragments [36].
• CONCLUSIONS: Most PSA in BPH nodules is in the nicked form with low chymotrypsin-like activity [37].
• The up-regulated PSA expression is a function of the level of the phosphorylated AR (r = 0.9814), but not the dephosphorylated form of the receptor protein (r = 0.4808) [38].

Co-localisations of KLK3

• The hGK-1 mRNA was colocalized with PSA mRNA in prostatic epithelia [39].

Regulatory relationships of KLK3

• Neutralizing antibodies to IL-6 blocked proliferation and expression of PSA by OCM [17].
• The production of PSA protein appears to be under the control of circulating androgens acting through the androgen receptor [40].
• EGFR signaling pathway negatively regulates PSA expression and secretion via the PI3K-Akt pathway in LNCaP prostate cancer cells [41].
• The chymotryptic activity of PSA was further confirmed by the ability of alpha-1-antichymotrypsin and chymostatin to block PSA cleavage of radiolabeled IGFBP-3.(ABSTRACT TRUNCATED AT 250 WORDS)[42]
• Recombinant prostin readily activates the precursor of PSA (pro-PSA) by cleavage of the amino terminal Arg(7)-Ile(8) peptide bond [43].

Other interactions of KLK3

• Whether hK2 can be expressed, like PSA, in nonprostatic cells is not known [26].
• 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 [44].
• These results demonstrate that IL-4 enhances PSA expression through activation of the AR and Akt signaling pathways in LNCaP prostate cancer cells [45].
• We speculate that PSA may serve to modulate IGF function within the reproductive system or in prostate cancer by altering IGF-IGFBP-3 interactions [34].
• IGFBP-2 and -4 in seminal plasma were not degraded by PSA [34].

Analytical, diagnostic and therapeutic context of KLK3

• The expression of KLK1 and KLK3 was further confirmed by sequence analysis of three different endometrial PCR products [23].
• Preoperative blood RT-PCR for PSA and hK2-U are neither therapy-guiding staging tools nor prognostic indicators in patients with clinically localized prostate cancer [3].
• Using a sensitive immunoassay with monoclonal antibodies to hK2, we found that T47-D cells could be induced with androgens, mineralocorticoids, glucocorticoids, and progestins to produce significantly more hK2 than PSA [26].
• Furthermore, electrophoretic mobility shift assay revealed that a putative transcriptional factor bound the GAGATA sequence in the PSA-producing prostate cancer cell [22].
• Significantly, the PSA levels fell to undetectable after nephrectomy [46].

References