The Experts below are selected from a list of 1560 Experts worldwide ranked by ideXlab platform
Eleftherios P Diamandis - One of the best experts on this subject based on the ideXlab platform.
-
Human tissue Kallikreins: Blood levels and response to radiotherapy in intermediate risk prostate cancer
Radiotherapy and Oncology, 2017Co-Authors: Nicola J Nasser, John Thoms, Antoninus Soosaipillai, Melania Pintilie, Eleftherios P Diamandis, Ri Wang, Robert G BristowAbstract:Abstract Objectives Kallikreins are serine proteases over expressed in many malignancies. In this study, we measure changes in serum kallikrein (KLKs) levels during intensity-modulated radiotherapy (IMRT) in prostate cancer patients, and find potential correlations between serum kallikrein level and normal tissues toxicity during radiation. Methods Forty-nine patients with prostate cancer were recruited as follows: group 1, definitive standard fractionation IMRT (78Gy in 39 fractions, n =15); group 2, definitive hypofractionated IMRT (60Gy in 20 fractions, n =15); and group 3, IMRT postprostatectomy (66Gy in 33 fractions, n =19). Patients treated with definitive radiation therapy were intermediate risk. Blood samples were collected at baseline and quarterly during IMRT and at each follow-up visit. Acute toxicity was graded weekly during radiotherapy using CTC-AE v4.0 criteria. Multiplexed immunoassays were used to quantify total, free, and intact Prostate Specific Antigen (PSA), as well as Kallikreins 2, 4, 6, and 11. Results The serum Kallikreins, PSA (total, free and intact), KLK2, 6, and 11 change significantly after definitive radiotherapy. KLK2 and intact PSA decrease as fast as two weeks after initiation of radiation, while the first significant decrease in total and free PSA is noted only at the completion of radiation. KLK6 and KLK11 surge temporarily during radiation therapy and decrease below baseline levels at 8weeks and 12months, respectively after completion of radiation. KLK4 levels did not change with radiation. There was no correlation between GU or GI toxicities and serum Kallikreins. Conclusions PSA, KLK2, 6, and 11, change significantly after definitive prostate radiotherapy, though KLK2 and PSA decrease by the end of the radiation course while KLK6 and KLK11 decrease significantly starting at 2 and 12months, respectively, after radiation. There was no correlation between GU or GI toxicities and serum Kallikreins.
-
human tissue Kallikreins as promiscuous modulators of homeostatic skin barrier functions
Biological Chemistry, 2008Co-Authors: Azza Eissa, Eleftherios P DiamandisAbstract:Human tissue Kallikreins (KLKs) are the largest family of secreted serine protease endopeptidases encoded by 15 genes clustered on chromosome 19q13.4. Multiple KLK enzymes are co-localized in the upper stratum granulosum and stratum corneum of human epidermis, and in associated appendages such as hair follicle epithelia and sweat glands. Until recently, kallikrein proteolytic activity in the skin was exclusively attributed to KLK5 and KLK7. However, wider cutaneous roles of Kallikreins became evident in recent years as the proposal of KLK proteolytic activation cascades emerged. We postulate that these proteolytic enzymes may serve as promiscuous mediators of different skin barrier functions, since they are capable of proteolysing different substrates that govern skin desquamation, antimicrobial defense, and lipid permeability. Growing evidence now attests to potential kallikrein involvement in skin inflammation, pigmentation, and tumor suppression via their ability to target proteinase-activated receptor signaling pathways. Current knowledge on kallikrein roles in skin physiology and pathobiology is described in this review.
-
a consolidated catalogue and graphical annotation of dbsnp polymorphisms in the human tissue kallikrein klk locus
Molecular Oncology, 2007Co-Authors: Carolyn A Goard, Eleftherios P Diamandis, Irvin L Bromberg, Marc B ElliottAbstract:Abstract The human tissue Kallikreins, 15 secreted serine proteases, may play diverse roles in pathophysiology. The National Center for Biotechnology Information's dbSNP was mined for polymorphisms located within the kallikrein ( KLK ) locus using custom-designed “ParSNPs” and “LocusAnnotator” software tools. Using “ParSNPs”, a filterable catalogue of 1856 KLK polymorphisms (1023 validated) was generated. “LocusAnnotator” was used to annotate the KLK locus sequence with gene and polymorphism features. A second locus was examined to validate the use of both programs on a non-kallikrein locus. This report may assist in the informed selection of KLK polymorphisms for future association and biochemical studies in relation to disease. Furthermore, “ParSNPs” and “LocusAnnotator” are available at no cost from our website ( www.acdcLab.org/annotations ) to examine other loci.
-
human tissue Kallikreins a road under construction
Clinica Chimica Acta, 2007Co-Authors: Nashmil Emami, Eleftherios P DiamandisAbstract:Abstract Background The human tissue kallikrein gene family, located at chromosome 19q13.4, is the largest contiguous family of proteases in the human genome. The locus encodes all 15 members of the family, 13 of which have been reported as potential biomarkers for several carcinomas and other non-neoplastic diseases. Kallikreins are expressed by a wide range of tissues and implicated in a number of physiological functions, including skin desquamation, semen liquefaction, neural plasticity and the regulation of blood pressure. Kallikrein function is regulated at various levels, including transcription, translation and post-translation. The proteolytic activity of Kallikreins is believed to be cascade mediated and may cross-talk with other proteases. These cascades are highly regulated through a series of feedback loops, inhibitors, (auto) degradation and internal cleavage. Uncontrolled proteolytic activity of Kallikreins is implicated in a large number of neoplastic and non-neoplastic pathological conditions. Conclusions As our understanding of their regulatory and functional mechanisms continues to expand, Kallikreins are expected to become novel targets for the design of new therapeutics.
-
human tissue Kallikreins the cancer biomarker family
Cancer Letters, 2007Co-Authors: Miltiadis Paliouras, Eleftherios P Diamandis, Carla A BorgonoAbstract:Human tissue Kallikreins (KLKs) are attracting increased attention due to their role as biomarkers for the screening, diagnosis, prognosis, and monitoring of various cancers including those of the prostate, ovarian, breast, testicular, and lung. Human tissue kallikrein genes represent the largest contiguous group of proteases within the human genome. Originally thought to consist of three genes, the identification of the human kallikrein locus has expanded this number to fifteen. These genes, and their encoded proteins, share a high degree of homology and are expressed in different tissues. Prostate-specific antigen (PSA), the most commonly known kallikrein, is a useful biomarker for prostate cancer. Several other Kallikreins, including Kallikreins 2 (KLK2) and 11 (KLK11) are emerging as complementary prostate cancer biomarkers. Along with these Kallikreins, several others have been implicated in the other cancers. For example, KLK5, 6, 7, 10, 11, and 14 are emerging biomarkers for ovarian cancer. The identification of kallikrein substrates and the development of proteolytic cascade models implicate kallikrein proteins in cancer progression. This review describes the current status of Kallikreins as cancer biomarkers.
George M Yousef - One of the best experts on this subject based on the ideXlab platform.
-
Kallikreins are involved in an miRNA network that contributes to prostate cancer progression.
Biological chemistry, 2014Co-Authors: Sara Samaan, Zsuzsanna Lichner, Qiang Ding, Carol Saleh, Joseph N. Samuel, Catherine J. Streutker, George M YousefAbstract:Abstract: MicroRNAs (miRNAs) are short RNA nucleo-tides that negatively regulate their target genes. They are differentially expressed in prostate cancer. Kallikreins are genes that encode serine proteases and are dysregu-lated in cancer. We elucidated a miRNA-kallikrein net-work that can be involved in prostate cancer progression. Target prediction identified 23 miRNAs that are dysregu-lated between high and low risk biochemical failure and are predicted to target five Kallikreins linked to prostate cancer; KLK2 , KLK3 , KLK4 , KLK14 and KLK15 . We also identified 14 miRNAs that are differentially expressed between Gleason grades and are predicted to target these Kallikreins. This demonstrates that Kallikreins are downstream effectors through which miRNAs influ-ence tumor progression. We show, through in-silico and experimental analysis, that miR-378/422a and its gene targets PIK3CG , GRB2 , AKT3 , KLK4 and KLK14 form an integrated circuit in prostate cancer. Our analysis shows that a minisatellite sequence in the kallikrein locus con-sists of a number of microsatellite repeats that represent predicted miRNA response elements. A number of kal-likrein and non-kallikrein prostate cancer-related genes share these microsatellite repeats. We validated some of these interactions in prostate cancer cell lines. Finally, we provide preliminary evidence on the presence of a miRNA-mediated cross-talk between Kallikreins, includ-ing a kallikrein pseudogene.
-
human tissue Kallikreins from gene structure to function and clinical applications
Advances in Clinical Chemistry, 2005Co-Authors: Christina V. Obiezu, George M Yousef, Liuying Luo, Angeliki Magklara, Carla A Borgono, Tadaaki KishiAbstract:Publisher Summary Kallikreins are expressed in many organs, most prominently in endocrine-related tissues such as the prostate, breast, ovary, uterus, vagina, and testis. The coexpression of many Kallikreins in several cancer types and other information pointing to the possibility of their involvement in a cascade-like pathway that may be associated with cancer pathogenesis or progression are presented in this chapter. Characterization and sequence analysis of human-tissue kallikrein gene locus are discussed in this chapter. A short historical perspective of the discovery of human-tissue kallikrein gene locus is presented in this chapter. Kallikreins in rodents and other species such as the mouse kallikrein gene family, the rat kallikrein gene family, and the dog kallikrein gene family are also described in this chapter. Structural features of human-tissue kallikrein genes and proteins such as common structural features and three-dimensional structure are also presented in this chapter. Sequence variations of human kallikrein genes, the tissue Kallikreins in the context of other serine proteases in the human genome, tissue expression and cellular localization of the kallikrein genes, regulation of kallikrein activity (at the mRNA level, at the protein level, locus control of kallikrein expression, and epigenetic regulation of kallikrein gene expression), hormonal regulation of Kallikreins, and evolution of Kallikreins are also presented in this chapter. Prognostic and predictive value of Kallikreins in hormone-dependent cancers such as ovarian cancer, breast cancer, and prostate cancer is also described in this chapter. The enzymatic activity of these serine proteases may initiate or terminate biological events. A third possible therapeutic approach involves immunotherapy or development of cancer vaccines. With increasing knowledge of the hormonal regulation of Kallikreins, hormonal activation (or repression) of kallikrein activity could be investigated in the future.
-
An update on human and mouse glandular Kallikreins.
Clinical Biochemistry, 2004Co-Authors: Eleftherios P Diamandis, George M Yousef, A. Yvonne OlssonAbstract:Human glandular Kallikreins are secreted serine proteases, involved in many biological processes. Recently, the complete organization of the human and mouse genomic loci has been elucidated. These loci harbor the largest clusters of serine proteases within the human and mouse genomes. Mouse orthologs to all human kallikrein genes, except for KLK2 and KLK3 genes, have now been identified. Here, we describe an update of the genomic organization of these families in human and mouse, and provide some thoughts for future research directions.
-
tissue Kallikreins new players in normal and abnormal cell growth
Thrombosis and Haemostasis, 2003Co-Authors: George M Yousef, Eleftherios P DiamandisAbstract:Serine proteases are proteolytic enzymes with an active serine residue in their catalytic site. Kallikreins are a subgroup of the serine protease family and are known to have diverse physiological functions. The human tissue kallikrein gene family has now been fully characterized and includes 15 members, clustered in a 300 kb region on chromosome 19q13.4. In this review, we discuss the common structural features of Kallikreins at the DNA, mRNA and protein levels. Kallikreins are secreted as inactive zymogens and are activated by cleavage of an N-terminal peptide. Some Kallikreins can undergo autoactivation while others may be activated by other Kallikreins or other proteases. Most Kallikreins are predicted to have trypsin-like enzymatic activity except for three members which may have chymotrypsin-like activity. Circumstantial evidence suggests that at least some Kallikreins may be part of an enzymatic cascade pathway which is activated in aggressive forms of ovarian and probably other cancers. Accumulating evidence suggests potential diagnostic and/or prognostic roles of Kallikreins in diverse malignancies. In addition to PSA, many other Kallikreins show differential expression in malignancy. For example, hK6, 10 and 11 are promising serological markers for ovarian cancer diagnosis. KLK10 may act as a tumor suppressor. In addition to their diagnostic and prognostic values, Kallikreins may also be good therapeutic targets.
-
Kallikreins steroid hormones and ovarian cancer is there a link
Minerva Endocrinologica, 2002Co-Authors: George M Yousef, Eleftherios P DiamandisAbstract:Kallikreins are a subgroup of serine proteases with diverse physiological functions. The human kallikrein gene family has now been fully characterized and includes 15 members tandemly located on chromosome 19q13.4. Strong experimental evidence supports a link between Kallikreins and endocrine malignancies and especially, ovarian cancer. Three new Kallikreins have been shown to be potential diagnostic and prognostic markers for ovarian cancer. Many other Kallikreins are also differentially expressed in ovarian cancer, and preliminary reports underline their possible prognostic value. The mechanism by which Kallikreins could be involved in ovarian cancer pathology is not known. A likely link could be their regulation through the steroid hormone receptor pathway. Most Kallikreins are under sex steroid hormonal regulation in cancer cell lines. Given the co-expression of many Kallikreins in ovarian cancer, it is reasonable to postulate that Kallikreins are involved in a cascade enzymatic pathway that plays a role in cancer progression. A multiparametric kallikrein expression profile may be a useful tool for ovarian cancer diagnosis/prognosis when used either alone or in conjunction with existing markers.
Julie Chao - One of the best experts on this subject based on the ideXlab platform.
-
Specificity determinants of rat tissue kallikrein probed by site-directed mutagenesis
2016Co-Authors: Jing Wang, Julie Chao, L E E ChaoAbstract:'To whom correspondence should be addressed Site-specific mutagenesis was employed to study structure-function relationships at the substrate binding site of rat tissue kallikrein. Four kallikrein mutants, the Pro219 deletion (P219del), the 34-38 loop Tyr-Tyr-Phe-Gly to Ile-Asn mutation [YYFG(34-38)IN], the Trp215-Gly exchange (W215G) and the double mutant with Tyr99—His and Trp215-Gly exchange (Y99H:W215G) were created by site-directed mutagenesis to probe their function in substrate binding. The mutant proteins were expressed in Escherichia coli at high levels and analyzed by Western blot. These mutant enzymes were purified to apparent homogeneity. Each migrated as a single band on SDS-PAGE, with slightly lower molecular mass (36 kDa) than that of the native enzyme, (38 kDa) because of their lack of glycosylation. The recombinant Kallikreins are immunologically identical to the native enzyme, displaying parallelism with the native enzyme in a direct radioimmunoassay for rat tissue kallikrein. Kinetic analyses of Km and kcat using fluorogenic peptide substrates support the hypothesis that the Tyr99-Trp215 interaction is a major determinant for hydrophobic P2 specificity. The results suggest an important role for the 34—38 loop in hydrophobic P3 affinity and further show that Pro219 is essential to substrate binding and efficient catalysis of tissue kallikrein. Key words: kallikrein/mutagenesis/serine proteinase/substrate specificit
-
nitric oxide mediates cardiac protection of tissue kallikrein by reducing inflammation and ventricular remodeling after myocardial ischemia reperfusion
Life Sciences, 2008Co-Authors: Hang Yin, L E E Chao, Julie ChaoAbstract:Abstract We assessed the role of nitric oxide (NO) and the kinin B2 receptor in mediating tissue kallikrein's actions in intramyocardial inflammation and cardiac remodeling after ischemia/reperfusion (I/R) injury. Adenovirus carrying the human tissue kallikrein gene was delivered locally into rat hearts 4 days prior to 30-minute ischemia followed by 24-hour or 7-day reperfusion with or without administration of icatibant, a kinin B2 receptor antagonist, or N(ω)–nitro–L–arginine methyl ester (L–NAME), a nitric oxide synthase inhibitor. Kallikrein gene delivery improved cardiac contractility and diastolic function, reduced infarct size at 1 day after I/R without affecting mean arterial pressure. Kallikrein treatment reduced macrophage/monocyte and neutrophil accumulation in the infarcted myocardium in association with reduced intercellular adhesion molecule-1 levels. Kallikrein increased cardiac endothelial nitric oxide synthase phosphorylation and NO levels and decreased superoxide formation, TGF–β1 levels and Smad2 phosphorylation. Furthermore, kallikrein reduced I/R-induced JNK, p38MAPK, IκB-α phosphorylation and nuclear NF–κB activation. In addition, kallikrein improved cardiac performance, reduced infarct size and prevented ventricular wall thinning at 7 days after I/R. The effects of kallikrein on cardiac function, inflammation and signaling mediators were all blocked by icatibant and L–NAME. These results indicate that tissue kallikrein through kinin B2 receptor and NO formation improves cardiac function, prevents inflammation and limits left ventricular remodeling after myocardial I/R by suppression of oxidative stress, TGF–β1/Smad2 and JNK/p38MAPK signaling pathways and NF–κB activation.
-
tissue kallikrein infusion prevents cardiomyocyte apoptosis inflammation and ventricular remodeling after myocardial infarction
Regulatory Peptides, 2007Co-Authors: Yuyu Yao, L E E Chao, Hang Yin, Bo Shen, Julie ChaoAbstract:Abstract We investigated the effect of tissue kallikrein infusion on cardiac protection at acute and sub-acute phases after myocardial infarction (MI). Immediately after MI, rats were infused with purified tissue kallikrein, with or without icatibant (a kinin B2 receptor antagonist). Intramyocardial injection of kallikrein reduced myocardial infarct size and inhibited cardiomyocyte apoptosis at 1 day after MI associated with increased nitric oxide levels, Akt and glycogen synthase kinase-3β phosphorylation and decreased caspase-3 activation. Kallikrein infusion for 7 days improved cardiac function, normalized left ventricular wall thickness and decreased monocyte/macrophage infiltration in the infarct heart. Kallikrein treatment reduced NADH oxidase expression and activity, superoxide formation and malondialdehyde levels, and reduced MAPK and Iκ-Bα phosphorylation, NF-κB activation and MCP-1 and VCAM-1 expression. Kallikrein's effects were all blocked by icatibant. These results indicate that kallikrein through kinin B2 receptor activation prevents apoptosis, inflammation and ventricular remodeling by increased nitric oxide formation and suppression of oxidative stress-mediated signaling pathways.
-
tissue kallikrein protects against pressure overload induced cardiac hypertrophy through kinin b2 receptor and glycogen synthase kinase 3β activation
Cardiovascular Research, 2007Co-Authors: Hang Yin, L E E Chao, Yuyu Yao, Bo Shen, Michael Bader, Julie ChaoAbstract:Objective: We assessed the role of glycogen synthase kinase-3β (GSK-3β) and kinin B2 receptor in mediating tissue kallikrein's protective effects against cardiac hypertrophy. Methods: We investigated the effect and mechanisms of tissue kallikrein using hypertrophic animal models of rats as well as mice deficient in kinin B1 or B2 receptor after aortic constriction (AC). Results: Intramyocardial delivery of adenovirus containing the human tissue kallikrein gene resulted in expression of recombinant kallikrein in rat myocardium. Kallikrein gene delivery improved cardiac function and reduced heart weight/body weight ratio and cardiomyocyte size without affecting mean arterial pressure 28 days after AC. Icatibant and adenovirus carrying a catalytically inactive GSK-3β mutant (Ad.GSK-3β-KM) abolished kallikrein's effects. Kallikrein treatment increased cardiac nitric oxide (NO) levels and reduced NAD(P)H oxidase activity and superoxide production. Furthermore, kallikrein reduced the phosphorylation of apoptosis signal-regulating kinase1, mitogen-activated protein kinases (MAPKs), Akt, GSK-3β, and cAMP-response element binding (CREB) protein, and decreased nuclear factor-κB (NF-κB) activation in the myocardium. Ad.GSK-3β-KM abrogated kallikrein's actions on GSK-3β and CREB phosphorylation and NF-κB activation, whereas icatibant blocked all kallikrein's effects. The protective role of kinin B2 receptor in cardiac hypertrophy was further confirmed in kinin receptor knockout mice as heart weight/body weight ratio and cardiomyocyte size increased significantly in kinin B2 receptor knockout mice after AC compared to wild type and B1 receptor knockout mice. Conclusions: These findings indicate that tissue kallikrein, through kinin B2 receptor and GSK-3β signaling, protects against pressure overload-induced cardiomyocyte hypertrophy by increased NO formation and oxidative stress-induced Akt-GSK-3β-mediated signaling events, MAPK and NF-κB activation.
-
the tissue kallikrein kinin system protects against cardiovascular and renal diseases and ischemic stroke independently of blood pressure reduction
Biological Chemistry, 2006Co-Authors: Julie Chao, Grant Bledsoe, Hang Yin, L E E ChaoAbstract:Tissue kallikrein (hK1) cleaves low-molecular-weight kininogen to produce kinin peptide, which binds to kinin receptors and triggers a wide spectrum of biological effects. Tissue kallikrein levels are reduced in humans and in animal models with hypertension, cardiovascular and renal diseases. Transgenic mice or rats over-expressing human tissue kallikrein or kinin B2 receptor are permanently hypotensive, and somatic kallikrein gene delivery reduces blood pressure in several hypertensive rat models. Moreover, kallikrein gene delivery or kallikrein protein infusion can directly improve cardiac, renal and neurological function without blood pressure reduction. Kallikrein has pleiotropic effects in inhibiting apoptosis, inflammation, proliferation, hypertrophy and fibrosis, and promoting angiogenesis and neurogenesis in different experimental animal models. Kallikrein's effects can be blocked by kinin B2 receptor antagonists. Mechanistically, tissue kallikrein/kinin leads to increased nitric oxide levels and Akt activation, and reduced reactive oxygen species formation, TGF-beta1 expression, MAPK and nuclear factor-kappaB activation. Our studies indicate that tissue kallikrein, through the kinin B2 receptor and nitric oxide formation, can protect against oxidative damage in cardiovascular and renal diseases and ischemic stroke. These novel findings suggest that kallikrein/kinin may serve as new drug targets for the prevention and treatment of heart failure, renal disease and stroke in humans.
Andreas Scorilas - One of the best experts on this subject based on the ideXlab platform.
-
Evolution of the Plasma and Tissue Kallikreins, and Their Alternative Splicing Isoforms
2016Co-Authors: Vassiliki Lila Koum, Andreas ScorilasAbstract:Kallikreins are secreted serine proteases with important roles in human physiology. Human plasma kallikrein, encoded by the KLKB1 gene on locus 4q34-35, functions in the blood coagulation pathway, and in regulating blood pressure. The human tissue kallikrein and kallikrein-related peptidases (KLKs) have diverse expression patterns and physiological roles, including cancer-related processes such as cell growth regulation, angiogenesis, invasion, and metastasis. Prostate-specific antigen (PSA), the product of the KLK3 gene, is the most widely used biomarker in clinical practice today. A total of 15 KLKs are encoded by the largest contiguous cluster of protease genes in the human genome (19q13.3-13.4), which makes them ideal for evolutionary analysis of gene duplication events. Previous studies on the evolution of KLKs have traced mammalian homologs as well as a probable early origin of the family in aves, amphibia and reptilia. The aim of this study was to address the evolutionary and functional relationships between tissue KLKs and plasma kallikrein, and to examine the evolution of alternative splicing isoforms. Sequences of plasma and tissue Kallikreins and their alternative transcripts were collected from the NCBI and Ensembl databases, and comprehensive phylogenetic analysis was performed by Bayesian as well as maximum likelihood methods. Plasma and tissue Kallikreins exhibit high sequence similarity in the trypsin domain (.50%). Phylogenetic analysis indicates an early divergence of KLKB1, which groups closely with plasminogen, chymotrypsin, and complement factor D (CFD), in a monophyletic group distinct from trypsin and the tissue KLKs. Reconstruction of th
-
Evolution of the Plasma and Tissue Kallikreins, and Their Alternative Splicing Isoforms
2013Co-Authors: Vassiliki Lila Koumandou, Andreas ScorilasAbstract:Kallikreins are secreted serine proteases with important roles in human physiology. Human plasma kallikrein, encoded by the KLKB1 gene on locus 4q34-35, functions in the blood coagulation pathway, and in regulating blood pressure. The human tissue kallikrein and kallikrein-related peptidases (KLKs) have diverse expression patterns and physiological roles, including cancer-related processes such as cell growth regulation, angiogenesis, invasion, and metastasis. Prostate-specific antigen (PSA), the product of the KLK3 gene, is the most widely used biomarker in clinical practice today. A total of 15 KLKs are encoded by the largest contiguous cluster of protease genes in the human genome (19q13.3-13.4), which makes them ideal for evolutionary analysis of gene duplication events. Previous studies on the evolution of KLKs have traced mammalian homologs as well as a probable early origin of the family in aves, amphibia and reptilia. The aim of this study was to address the evolutionary and functional relationships between tissue KLKs and plasma kallikrein, and to examine the evolution of alternative splicing isoforms. Sequences of plasma and tissue Kallikreins and their alternative transcripts were collected from the NCBI and Ensembl databases, and comprehensive phylogenetic analysis was performed by Bayesian as well as maximum likelihood methods. Plasma and tissue Kallikreins exhibit high sequence similarity in the trypsin domain (>50%). Phylogenetic analysis indicates an early divergence of KLKB1, which groups closely with plasminogen, chymotrypsin, and complement factor D (CFD), in a monophyletic group distinct from trypsin and the tissue KLKs. Reconstruction of the earliest events leading to the diversification of the tissue KLKs is not well resolved, indicating rapid expansion in mammals. Alternative transcripts of each KLK gene show species-specific divergence, while examination of sequence conservation indicates that many annotated human KLK isoforms are missing the catalytic triad that is crucial for protease activity.
-
serum and urine tissue kallikrein concentrations in male to female transsexuals treated with antiandrogens and estrogens
Clinical Chemistry, 2006Co-Authors: Margrita H Slagter, Antoninus Soosaipillai, Andreas Scorilas, Miltiadis Paliouras, L J G Gooren, Willem De Ronde, Erik J Giltay, Eleftherios P DiamandisAbstract:Background: The expression of human tissue kallikrein genes is regulated by steroid hormones, but most studies have been conducted with cancer cell lines. Our purpose was to examine serum and urinary tissue kallikrein concentration changes in male-to-female transsexuals before and after treatment with antiandrogens and estrogens. Methods: Thirty-five male-to-female transsexuals receiving cyproterone acetate and estrogens (orally or transdermally) were included in this study. Serum and urine samples were collected before initiation of therapy and 4 and 12 months post therapy. ELISAs were used to measure multiple Kallikreins in serum and urine. Results: After antiandrogen and estrogen therapy, serum testosterone concentrations decreased dramatically, as did serum and urinary concentrations of human glandular kallikrein (hK2) and prostate-specific antigen (PSA; hK3). Statistically significant but relatively small changes in serum and urinary concentrations of many other Kallikreins were also seen. Kallikreins in serum and urine were correlated before and after treatment. Conclusions: The concentrations of hK2 and hK3, but not of any other Kallikreins, decrease dramatically after combined antiandrogen and estrogen treatment in male-to-female transsexuals. The smaller responses of the other Kallikreins presumably reflect their expression in multiple tissues.
-
expression analysis of the human kallikrein 7 klk7 in breast tumors a new potential biomarker for prognosis of breast carcinoma
Thrombosis and Haemostasis, 2003Co-Authors: Maroulio Talieri, Eleftherios P Diamandis, Dimitrios Gourgiotis, Kostandina Mathioudaki, Andreas ScorilasAbstract:Kallikreins are a subgroup of serine proteases that are involved in the post-translational processing of polypeptide precursors. Growing evidence suggests that many Kallikreins are implicated in carcinogenesis. Human kallikrein gene 7 (KLK7; HSCCE) is a new member of the human kallikrein gene family. KLK7 is expressed in normal breast tissue and is up-regulated in breast cancer cells by estrogens and glucocorticoids. In the present study, expression of the KLK7 gene in 92 breast cancer tissues was analyzed by reverse transcription-PCR (RT-PCR) and direct sequencing of several samples. The results were correlated with other clinicopathological variables and patient outcome. KLK7 gene expression was significantly lower in breast cancer patients of low stage (I/II) (p = 0.011) and patients with positive progesterone receptors (p = 0.022). Survival analysis showed that breast cancer patients with KLK7 positive tumors have relatively shorter disease-free survival (DFS) and overall survival (OS) than patients with KLK7 negative tumors. These data suggest that KLK7 gene expression may be used as a marker of unfavorable prognosis for breast cancer patients.
-
genomic organization of the human kallikrein gene family on chromosome 19q13 3 q13 4
Biochemical and Biophysical Research Communications, 2000Co-Authors: Albert Chang, George M Yousef, Andreas Scorilas, Eleftherios P DiamandisAbstract:Abstract Kallikreins are a subgroup of serine proteases with diverse physiological functions. Recently, growing evidence indicates that many kallikrein genes are involved in malignancy. In rodents, Kallikreins are encoded by a large multigene family, but in humans only three Kallikreins were thought to exist. Based on the homology between the human and rodent kallikrein loci, we studied a 300 kb region of genomic sequences around the putative KLK1 gene locus on chromosome 19q13.3–q13.4. By using linear sequence information, restriction analysis, end sequencing, PCR and blotting techniques, as well as bioinformatic approaches, we were able to construct the first detailed map of the human kallikrein gene family. Comparative analysis of genes located in this area, provides strong evidence that the human kallikrein gene family locus on chromosome 19 is considerably larger than previously thought, containing at least fifteen genes. We have established, for the first time, the common structural features that apply to all members of the expanded kallikrein multigene family. Our map specifies the distance between genes to one base pair accuracy, the relative location, and the direction of transcription of all 15 genes. Determination of the true size of the kallikrein family in humans is important for our understanding of the contribution of the Kallikreins to human biology and pathophysiology.
Judith A. Clements - One of the best experts on this subject based on the ideXlab platform.
-
Kallikreins on Steroids: Structure, Function, and Hormonal Regulation of Prostate-Specific Antigen and the Extended Kallikrein Locus
Endocrine Reviews, 2010Co-Authors: Mitchell G. Lawrence, Judith A. ClementsAbstract:The 15 members of the kallikrein-related serine peptidase (KLK) family have diverse tissue-specific expression profiles and putative proteolytic functions. The kallikrein family is also emerging as a rich source of disease biomarkers with KLK3, commonly known as prostate-specific antigen, being the current serum biomarker for prostate cancer. The kallikrein locus is also notable because it is extraordinarily responsive to steroids and other hormones. Indeed, at least 14 functional hormone response elements have been identified in the kallikrein locus. A more comprehensive understanding of the transcriptional regulation of Kallikreins may help the field make more informed hypotheses about the physiological functions of Kallikreins and their effectiveness as biomarkers. In this review, we describe the organization of the kallikrein locus and the structure of kallikrein genes and proteins. We also focus on the transcriptional regulation of Kallikreins by androgens, progestins, glucocorticoids, mineralocorticoids, estrogens, and other hormones in animal models and human prostate, breast, and reproductive tract tissues. The interaction of the androgen receptor with androgen response elements in the promoter and enhancer of KLK2 and KLK3 is also summarized in detail. There is evidence that all Kallikreins are regulated by multiple nuclear receptors. Yet, apart from KLK2 and KLK3, it is not clear whether all Kallikreins are direct transcriptional targets. Therefore, we argue that gaining more detailed information about the mechanisms that regulate kallikrein expression should be a priority of future studies and that the kallikreinlocuswillcontinuetobeanimportantmodelintheeraofgenome-wideanalyses.(EndocrineReviews 31: 407–446, 2010)
-
the tissue kallikrein family of serine proteases functional roles in human disease and potential as clinical biomarkers
Critical Reviews in Clinical Laboratory Sciences, 2004Co-Authors: Judith A. Clements, Stephen Myers, Nicole M Willemsen, Ying DongAbstract:Prostate specific antigen (PSA) or human kallikrein 3 (hK3) has long been an effective biomarker for prostate cancer. Now, other members of the tissue kallikrein (KLK) gene family are fast becoming of clinical interest due to their potential as prognostic biomarkers, particularly for hormone dependent cancers. The tissue Kallikreins are serine proteases that are encoded by highly conserved multi-gene family clusters in rodents and humans. The rat and mouse loci contain 10 and 25 functional genes, respectively, while the human locus at 19q 13.4 contains 15 genes. The structural organization and size of these genes are similar across species; all genes have 5 coding exons that encode a prepro-enzyme. Although the physiological activators of these zymogens have not been described, in vitro biochemical studies show that some Kallikreins can auto-activate and others can activate each other, suggesting that the Kallikreins may participate in an enzymatic cascade similar to that of the coagulation cascade. These genes are expressed, to varying degrees, in a wide range of tissues suggesting a functional involvement in a diverse range of physiological and pathophysiological processes. These include roles in normal skin desquamation and psoriatic lesions, tooth development, neural plasticity, and Alzheimer's disease (AD). Of particular interest is the expression of many Kallikreins in prostate, ovarian, and breast cancers where they are emerging as useful prognostic indicators of disease progression.
-
Identification and characterization of KLK14, a novel kallikrein serine protease gene located on human chromosome 19q13.4 and expressed in prostate and skeletal muscle.
Genomics, 2001Co-Authors: John D Hooper, Tracey J. Harvey, Stephen Myers, Linda K Ashworth, Loan Bui, Fiona K. Rae, Judith A. ClementsAbstract:The Kallikreins are a subfamily of serine proteases encoded in human, mouse, and rat by highly conserved tightly clustered multigene families. Here we report the identification and characterization of KLK14, a novel kallikrein gene located within the human kallikrein locus at 19q13.4. KLK14 is approximately 5.4 kb in length spanning seven exons and, by Northern blot analysis, transcribes two alternative transcripts present only in prostate (1.5 kb) and skeletal muscle (1.9 kb). The protein product, K14, predicted to be a 251-amino-acid secreted serine protease with trypsin-like substrate specificity, is translated in vitro with a molecular mass of approximately 31 kDa. 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.
-
The Expanded Human Kallikrein (KLK) gene family : genomic organisation, tissue specific expression and potential functions
Biological Chemistry, 2001Co-Authors: Judith A. Clements, John D Hooper, Ying Dong, Tracey J. HarveyAbstract:The tissue Kallikreins are serine proteases encoded by highly conserved multigene families. The rodent kallikrein (KLK) families are particularly large, consisting of 13 26 genes clustered in one chromosomal locus. It has been recently recognised that the human KLK gene family is of a similar size (15 genes) with the identification of another 12 related genes (KLK4-KLK15) within and adjacent to the original human KLK locus (KLK1-3) on chromosome 19q13.4. The structural organisation and size of these new genes is similar to that of other KLK genes except for additional exons encoding 5 or 3 untranslated regions. Moreover, many of these genes have multiple mRNA transcripts, a trait not observed with rodent genes. Unlike all other Kallikreins, the KLK4-KLK15 encoded proteases are less related (25–44%) and do not contain a conventional kallikrein loop. Clusters of genes exhibit high prostatic (KLK2-4, KLK15) or pancreatic (KLK6-13) expression, suggesting evolutionary conservation of elements conferring tissue specificity. These genes are also expressed, to varying degrees, in a wider range of tissues suggesting a functional involvement of these newer human kallikrein proteases in a diverse range of physiological processes.
-
New nomenclature for the human tissue kallikrein gene family
Clinical Chemistry, 2000Co-Authors: Eleftherios P Diamandis, Shigetaka Yoshida, Sheila P. Little, George M Yousef, Linda K Ashworth, Peter S Nelson, Torbjörn Egelrud, Judith A. Clements, Sadao Shiosaka, Hans LiljaAbstract:The human kallikrein gene family is important to the discipline of clinical chemistry because it contains genes that encode for valuable cancer biomarkers, including the best tumor marker available today, prostate-specific antigen (PSA). Despite reports of numerous kallikrein-like genes in the mouse (1), until 2–3 years ago, only three human kallikrein genes were recognized: pancreatic/renal kallikrein (KLK1) , human glandular kallikrein 2 (KLK2) , and prostate-specific antigen (KLK3) (1)(2). The proteins encoded by the three kallikrein genes are now known as hK1, hK2, and hK3 (PSA). These three genes encode for serine proteases with either trypsin-like (hK1, hK2) or chymotrypsin-like (hK3) activity. Traditionally, Kallikreins have been defined as enzymes that can act on high-molecular weight substrates and release bioactive peptides, known as kinins (3). Among the known kallikrein enzymes, only plasma kallikrein (encoded by a single gene localized on human chromosome 4q35; official symbol KLKB1 ) and pancreatic/renal kallikrein (hK1) have significant kininogenase activity. The proteins encoded by the KLK2 and the KLK3 genes have minimal or no kininogenase activity (4)(5). Why then are the KLK1 , KLK2 , and KLK3 genes classified together into one gene family (tissue kallikrein gene family), when two of the three enzymes have no significant kallikrein enzymatic activity? This grouping is justified, based on the extensive homologies between the three genes at both the DNA …
