Zeitschriftenartikel: „Kallikrein-Related peptidase 5“

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Ismail, Maha Imam Ahmed, *. Manal Basyouni Ahmed * Manal Basyouni Ahmed und Muneera Al-Sheeha. „Evaluation of kallikrein-related peptidase 5 [KLK5] and Survivin as Prognostic Markers in Breast Cancer“. International Journal of Scientific Research 3, Nr. 5 (01.06.2012): 398–401. http://dx.doi.org/10.15373/22778179/may2014/124.

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Zingkou, Eleni, Georgios Pampalakis und Georgia Sotiropoulou. „Exacerbated dandruff in the absence of kallikrein‐related peptidase 5 protease“. Journal of Dermatology 47, Nr. 3 (07.01.2020): 311–13. http://dx.doi.org/10.1111/1346-8138.15174.

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Sidiropoulos, Konstantinos G., Nicole M. A. White, Anna Bui, Qiang Ding, Peter Boulos, Georgios Pampalakis, Heba Khella, Joseph N. Samuel, Georgia Sotiropoulou und George M. Yousef. „Kallikrein-related peptidase 5 induces miRNA-mediated anti-oncogenic pathways in breast cancer“. Oncoscience 1, Nr. 11 (24.10.2014): 709–24. http://dx.doi.org/10.18632/oncoscience.91.

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Malachias, Apostolos, Georgia Papachristopoulou, Dimitrios Kypraios, Stefanos P. Bassioukas, Maria Nikaki, Dimitrios Xinopoulos und Maroulio Talieri. „Sa1973 Analysis and Clinical Evaluation of Kallikrein-Related Peptidase 5 (KLK5) in Colon Cancer“. Gastroenterology 148, Nr. 4 (April 2015): S—372. http://dx.doi.org/10.1016/s0016-5085(15)31246-4.

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Ortloff, A., F. A. Bustamante, L. Molina, J. Ojeda, C. D. Figueroa und P. Ehrenfeld. „Kallikrein-related Peptidase 5 (KLK5) Expression and Distribution in Canine Cutaneous Squamous Cell Carcinoma“. Journal of Comparative Pathology 174 (Januar 2020): 113–19. http://dx.doi.org/10.1016/j.jcpa.2019.11.009.

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Sakabe, Jun-ichi, Mami Yamamoto, Satoshi Hirakawa, Akira Motoyama, Isao Ohta, Kazuki Tatsuno, Taisuke Ito, Kenji Kabashima, Toshihiko Hibino und Yoshiki Tokura. „Kallikrein-related Peptidase 5 Functions in Proteolytic Processing of Profilaggrin in Cultured Human Keratinocytes“. Journal of Biological Chemistry 288, Nr. 24 (29.04.2013): 17179–89. http://dx.doi.org/10.1074/jbc.m113.476820.

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Lin, Yongbo, Li Ma, Hanliang Dan, Gang Chen, Jian Dai, Liang Xu und Yuqi Liu. „MiR-107-3p Knockdown Alleviates Endothelial Injury in Sepsis via Kallikrein-Related Peptidase 5“. Journal of Surgical Research 292 (Dezember 2023): 264–74. http://dx.doi.org/10.1016/j.jss.2023.07.013.

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Yoon, Hyesook, und Isobel A. Scarisbrick. „Kallikrein-related peptidase 6 exacerbates disease in an autoimmune model of multiple sclerosis“. Biological Chemistry 397, Nr. 12 (01.12.2016): 1277–86. http://dx.doi.org/10.1515/hsz-2016-0239.

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Abstract Kallikrein-related peptidase 6 (Klk6) is elevated in the serum of multiple sclerosis (MS) patients and is hypothesized to participate in inflammatory and neuropathogenic aspects of the disease. To test this hypothesis, we investigated the impact of systemic administration of recombinant Klk6 on the development and progression of MOG35-55-induced experimental autoimmune encephalomyelitis (EAE). First, we determined that Klk6 expression is elevated in the spinal cord of mice with EAE at the peak of clinical disease and in immune cells upon priming with the disease-initiating peptide in vitro. Systemic administration of recombinant Klk6 to mice during the priming phase of disease resulted in an exacerbation of clinical symptoms, including earlier onset of disease and higher levels of spinal cord inflammation and pathology. Treatment of MOG35-55-primed immune cells with Klk6 in culture enhanced expression of pro-inflammatory cytokines, interferon-γ, tumor necrosis factor, and interleukin-17, while reducing anti-inflammatory cytokines interleukin-4 and interleukin-5. Together these findings provide evidence that elevations in systemic Klk6 can bias the immune system towards pro-inflammatory responses capable of exacerbating the development of neuroinflammation and paralytic neurological deficits. We suggest that Klk6 represents an important target for conditions in which pro-inflammatory responses play a critical role in disease development, including MS.

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Wu, Yanhua, Yingjian Chen, Qing Li, Yanwen Gong, Xiaohong Liu, Liquan Bi und Chengjin Hu. „Upregulation of kallikrein-related peptidase 5 is associated with the malignant behavior of colorectal cancer“. Molecular Medicine Reports 14, Nr. 3 (13.07.2016): 2164–70. http://dx.doi.org/10.3892/mmr.2016.5516.

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Petraki, Constantina, Youssef M. Youssef, William Dubinski, Zsuzsanna Lichner, Andreas Scorilas, Maria D. Pasic, Vassilios Komborozos et al. „Evaluation and prognostic significance of human tissue kallikrein-related peptidase 10 (KLK10) in colorectal cancer“. Tumor Biology 33, Nr. 4 (22.03.2012): 1209–14. http://dx.doi.org/10.1007/s13277-012-0368-5.

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Magnen, Mélia, Brigitta Margit Elsässer, Olga Zbodakova, Petr Kasparek, Fabien Gueugnon, Agnès Petit-Courty, Radislav Sedlacek, Peter Goettig und Yves Courty. „Kallikrein-related peptidase 5 and seasonal influenza viruses, limitations of the experimental models for activating proteases“. Biological Chemistry 399, Nr. 9 (25.09.2018): 1053–64. http://dx.doi.org/10.1515/hsz-2017-0340.

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Abstract Every year, influenza A virus (IAV) affects and kills many people worldwide. The viral hemagglutinin (HA) is a critical actor in influenza virus infectivity which needs to be cleaved by host serine proteases to exert its activity. KLK5 has been identified as an activating protease in humans with a preference for the H3N2 IAV subtype. We investigated the origin of this preference using influenza A/Puerto Rico/8/34 (PR8, H1N1) and A/Scotland/20/74 (Scotland, H3N2) viruses. Pretreatment of noninfectious virions with human KLK5 increased infectivity of Scotland IAV in MDCK cells and triggered influenza pneumonia in mice. These effects were not observed with the PR8 IAV. Molecular modeling and in vitro enzymatic studies of peptide substrates and recombinant HAs revealed that the sequences around the cleavage site do not represent the sole determinant of the KLK5 preference for the H3N2 subtype. Using mouse Klk5 and Klk5-deficient mice, we demonstrated in vitro and in vivo that the mouse ortholog protease is not an IAV activating enzyme. This may be explained by unfavorable interactions between H3 HA and mKlk5. Our data highlight the limitations of some approaches used to identify IAV-activating proteases.

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Montenegro, Sara Estefania, Jang-Hee Oh, Joong Heon Suh, Je-Ho Mun und Jin Ho Chung. „Higher Expression of Lympho-epithelial Kazal-type-Related Inhibitor-1 Fragments and Decreased Desquamation in the Lesional Skin of Nummular Eczema“. Acta Dermato-Venereologica 104 (29.03.2024): adv188636. http://dx.doi.org/10.2340/actadv.v104.18636.

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Nummular eczema, a chronic dermatitis characterized by coin-shaped lesions, was first documented in 1857. However, its pathophysiological characteristics are still not well known. To investigate differences in the regulation of the desquamation process in the stratum corneum of lesional and nonlesional skin of patients with nummular eczema and healthy control subjects, tape-stripped stratum corneum samples from patients with nummular eczema and healthy volunteers were analysed using immunofluorescence staining and western blot analysis. In the nummular eczema lesional skin, expression of desmoglein-1, desmocollin-1, and corneodesmosin exhibited a disorganized, dense or partially diffuse non-peripheral pattern with increased intensity, compared with the peripheral patterns observed in healthy or nonlesional skin, suggesting the impaired desquamation process in nummular eczema. Furthermore, although the expression of the desquamation-related serine proteases, kallikrein-related peptidase 7 and 5, was increased in nummular eczema lesional skin, the immunofluorescence staining of lympho-epithelial Kazal-type-related inhibitor-1, an endogenous inhibitor of various kallikrein-related peptidases, and its fragments were significantly increased in the nummular eczema lesional skin, suggesting its contribution to the inhibition of corneodesmosomal degradation. Therefore, the increased detection of corneodesmosomal proteins in nummular eczema lesions may be due to the increased amount of the fragments of lympho-epithelial Kazal-type-related inhibitor-1, which could contribute to delayed desquamation.

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Nohara, Kyoko, Kazuhiko Yamada, Leo Yamada, Teruki Hagiwara, Toru Igari, Chizu Yokoi, Daisuke Soma, Satoshi Yamashita, Taeko Dohi und Yuki I. Kawamura. „Expression of kallikrein-related peptidase 13 is associated with poor prognosis in esophageal squamous cell carcinoma“. General Thoracic and Cardiovascular Surgery 66, Nr. 6 (26.03.2018): 351–57. http://dx.doi.org/10.1007/s11748-018-0910-5.

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Lee, Chia-Yao, David Marzan, Grace Lin, Steve Goodison und Steve Silletti. „α2 Integrin-Dependent Suppression of Pancreatic Adenocarcinoma Cell Invasion Involves Ectodomain Regulation of Kallikrein-Related Peptidase-5“. Journal of Oncology 2011 (2011): 1–15. http://dx.doi.org/10.1155/2011/365651.

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Previous reports demonstrate that the α2-integrin (α2) mediates pancreatic ductal adenocarcinoma (PDAC) cell interactions with collagens. We found that while well-differentiated cells use α2 exclusively to adhere and migrate on collagenI, poorly differentiated PDAC cells demonstrate reduced reliance on, or complete loss of, α2. Since well-differentiated PDAC lines exhibit reducedin vitroinvasion and α2-blockade suppressed invasion of well-differentiated lines exclusively, we hypothesized that α2 may suppress the malignant phenotype in PDAC. Accordingly, ectopic expression of α2 retardedin vitroinvasion and maintenance on collagenI exacerbated this effect. Affymetrix profiling revealed that kallikrein-related peptidase-5 (KLK5) was specifically upregulated by α2, and reduced α2 and KLK5 expression was observed in poorly differentiated PDAC cellsin situ. Accordingly, well-differentiated PDAC lines express KLK5, and KLK5 blockade increased the invasion of KLK5-positive lines. The α2-cytoplasmic domain was dispensable for these effects, demonstrating that the α2-ectodomain and KLK5 coordinately regulate a less invasive phenotype in PDAC.

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de Veer, Simon J., Joakim E. Swedberg, Maria Brattsand, Judith A. Clements und Jonathan M. Harris. „Exploring the active site binding specificity of kallikrein-related peptidase 5 (KLK5) guides the design of new peptide substrates and inhibitors“. Biological Chemistry 397, Nr. 12 (01.12.2016): 1237–49. http://dx.doi.org/10.1515/hsz-2016-0112.

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Abstract Kallikrein-related peptidase 5 (KLK5) is a promising therapeutic target in several skin diseases, including Netherton syndrome, and is emerging as a potential target in various cancers. In this study, we used a sparse matrix library of 125 individually synthesized peptide substrates to characterize the binding specificity of KLK5. The sequences most favored by KLK5 were GRSR, YRSR and GRNR, and we identified sequence-specific interactions involving the peptide N-terminus by analyzing kinetic constants (kcat and KM) and performing molecular dynamics simulations. KLK5 inhibitors were subsequently engineered by substituting substrate sequences into the binding loop (P1, P2 and P4 residues) of sunflower trypsin inhibitor-1 (SFTI-1). These inhibitors were effective against KLK5 but showed limited selectivity, and performing a further substitution at P2′ led to the design of a new variant that displayed improved activity against KLK5 (Ki=4.2±0.2 nm), weak activity against KLK7 and 12-fold selectivity over KLK14. Collectively, these findings provide new insight into the design of highly favored binding sequences for KLK5 and reveal several opportunities for modulating inhibitor selectivity over closely related proteases that will be useful for future studies aiming to develop therapeutic molecules targeting KLK5.

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Papachristopoulou, Georgia, Apostolos Malachias, Marina Devetzi, Evdoxia Kamouza, Andreas Scorilas, Dimitris Xynopoulos und Maroulio Talieri. „Uncovering the clinical impact of kallikrein-related peptidase 5 (KLK5) mRNA expression in the colorectal adenoma-carcinoma sequence“. Clinical Chemistry and Laboratory Medicine (CCLM) 57, Nr. 8 (26.07.2019): 1251–60. http://dx.doi.org/10.1515/cclm-2018-1010.

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Abstract Background Kallikrein-related peptidases (KLKs) are a subgroup of serine proteases located on chromosome 19q13.3. Most KLKs have been extensively studied as potential biomarkers for several carcinomas and other diseases. KLK5 was originally identified from a keratinocyte library, and its enzyme was purified from the stratum corneum of human skin. KLK5 was shown to be differentially expressed in a variety of endocrine tumors, although it is not as yet examined widely in colorectal cancer (CRC). Methods In this study, we quantitatively assessed the mRNA expression status of KLK5 in 197 colorectal tissues from 133 patients (70 cancerous and their paired normal colonic mucosa for 64 of them, as well as 63 colorectal adenomas) by quantitative real-time PCR (qPCR) using TaqMan probes. Statistical analysis evaluated the results. Results It was shown that KLK5 expression is reduced following the histologically non-cancerous-adenoma sequence (p<0.001), whereas it is increased during the sequence adenoma-carcinoma (p<0.001). Furthermore, KLK5 positive expression is associated with positive nodal status (p=0.022), advanced tumor stage (p=0.038) and high histological grade (p=0.033). Cox univariate analysis revealed that KLK5 positive expression is associated with disease-free survival (DFS) (p=0.028) and overall survival (OS) of patients (p=0.048). Kaplan-Meyer survival models showed that patients with positive KLK5 expression have lower DFS (p=0.009) and OS (p=0.019). Receiver operating characteristic (ROC) analysis demonstrated for first time that KLK5 expression had significant discriminatory values between cancer and adenoma tissues (area under the curve [AUC] 0.77; 95% confidence interval [CI]=0.69–0.85, p=0.03). Conclusions KLK5 mRNA expression may be useful for the differentiation of CRC from colorectal adenoma and represents a potential unfavorable prognostic biomarker for CRC.

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Bandiera, Elisabetta, Laura Zanotti, Eliana Bignotti, Chiara Romani, Renata Tassi, Paola Todeschini, Germana Tognon et al. „Human Kallikrein 5: An Interesting Novel Biomarker in Ovarian Cancer Patients That Elicits Humoral Response“. International Journal of Gynecologic Cancer 19, Nr. 6 (Juli 2009): 1015–21. http://dx.doi.org/10.1111/igc.0b013e3181ab597f.

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Introduction:Kallikrein-related peptidases are secreted serine proteases that exert stimulatory or inhibitory effects on tumor progression. A recent study demonstrated that kallikrein-related peptidase 5 (KLK5) concentration is elevated in serum of patients with ovarian carcinoma. At the moment, the presence of KLK5 in other ovarian pathological lesions is not clearly determined. Moreover, the possibility of a spontaneous humoral immune response to KLK5 has not been studied yet.Methods:In this study, we examined KLK5 levels and antibody (IgG and IgM) response to KLK5 in the serum of 50 healthy women, 50 patients with benign pelvic masses, 17 patients with ovarian borderline tumors, and 50 patients with ovarian carcinomas, using 3 enzyme-linked immunosorbent assay tests available in-house.Results:At 95% specificity on healthy controls, 52% of patients with ovarian carcinoma showed high serum KLK5 (sKLK5) levels, whereas patients with benign pathological lesions or borderline tumors showed almost undetectable sKLK5 levels. Moreover, sKLK5 levels were positively associated to International Federation of Gynaecologists and Obstetricians stage suggesting a possible role of sKLK5 in ovarian cancer progression. Our results about humoral response showed elevated levels of KLK5-specific antibodies in 20% of patients with benign masses, 26% of patients with borderline tumors, and 36% of patients with ovarian carcinomas when compared with healthy controls. Interestingly, KLK5 antibodies were also found in patients with undetectable sKLK5 levels.Conclusions:In conclusion, our results showed that KLK5 is a potential new biomarker to be used in combination with other biomarkers for ovarian cancer detection. Moreover, the existence of KLK5 antibodies suggests that KLK5 might represent a possible target for immune-based therapies.

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Pampalakis, Georgios, Eleni Zingkou und Georgia Sotiropoulou. „KLK5, a novel potential suppressor of vaginal carcinogenesis“. Biological Chemistry 399, Nr. 9 (25.09.2018): 1107–11. http://dx.doi.org/10.1515/hsz-2017-0302.

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Abstract Vaginal cancer is rare and largely unexplored. We found here that kallikrein-related peptidase 5 (KLK5) is coordinately expressed along with other KLKs in all stratified epithelia, including vagina, pointing to potential role(s) in differentiation. Further, we propose that KLK5 could be implicated in vaginal cancer development based on the fact that Klk5−/− mice are prone to develop vaginal tumors when exposed to 7,12-dimethylbenz[a]anthracene. Nf-κb activation is markedly enhanced in Klk5−/−, leading to increased resistance to apoptosis of mutated vaginal cells. This explains the higher tumor numbers observed in Klk5−/− compared to wildtype. Thus, KLK5 may represent a putative suppressor of vaginal cancer.

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Furio, Laetitia, Simon de Veer, Madeleine Jaillet, Anais Briot, Aurelie Robin, Celine Deraison und Alain Hovnanian. „Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome“. Journal of Experimental Medicine 211, Nr. 3 (17.02.2014): 499–513. http://dx.doi.org/10.1084/jem.20131797.

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Netherton syndrome (NS) is a severe genetic skin disease in which absence of a key protease inhibitor causes congenital exfoliative erythroderma, eczematous-like lesions, and atopic manifestations. Several proteases are overactive in NS, including kallikrein-related peptidase (KLK) 5, KLK7, and elastase-2 (ELA2), which are suggested to be part of a proteolytic cascade initiated by KLK5. To address the role of KLK5 in NS, we have generated a new transgenic murine model expressing human KLK5 in the granular layer of the epidermis (Tg-KLK5). Transgene expression resulted in increased proteolytic activity attributable to KLK5 and its downstream targets KLK7, KLK14, and ELA2. Tg-KLK5 mice developed an exfoliative erythroderma with scaling, growth delay, and hair abnormalities. The skin barrier was defective and the stratum corneum was detached through desmosomal cleavage. Importantly, Tg-KLK5 mice displayed cutaneous and systemic hallmarks of severe inflammation and allergy with pruritus. The skin showed enhanced expression of inflammatory cytokines and chemokines, infiltration of immune cells, and markers of Th2/Th17/Th22 T cell responses. Moreover, serum IgE and Tslp levels were elevated. Our study identifies KLK5 as an important contributor to the NS proteolytic cascade and provides a new and viable model for the evaluation of future targeted therapies for NS or related diseases such as atopic dermatitis.

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Wu, Yanhua, Xiaofei Liu, Yingjian Chen und Chengjin Hu. „Development and evaluation of an ELISA method for the measurement of kallikrein-related peptidase 5 (KLK5) in human serum“. Open Journal of Clinical Diagnostics 03, Nr. 04 (2013): 159–66. http://dx.doi.org/10.4236/ojcd.2013.34029.

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Meyer-Hoffert, Ulf, Zhihong Wu und Jens-Michael Schröder. „Identification of Lympho-Epithelial Kazal-Type Inhibitor 2 in Human Skin as a Kallikrein-Related Peptidase 5-Specific Protease Inhibitor“. PLoS ONE 4, Nr. 2 (03.02.2009): e4372. http://dx.doi.org/10.1371/journal.pone.0004372.

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Planque, Chris, Yun-Hee Choi, Serge Guyetant, Nathalie Heuzé-Vourc'h, Laurent Briollais und Yves Courty. „Alternative Splicing Variant of Kallikrein-Related Peptidase 8 as an Independent Predictor of Unfavorable Prognosis in Lung Cancer“. Clinical Chemistry 56, Nr. 6 (01.06.2010): 987–97. http://dx.doi.org/10.1373/clinchem.2009.138917.

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Abstract Background: A relatively unexplored area for biomarker identification is alternative splice variants. We undertook this study to evaluate the usefulness of mRNA isoforms encoded by the KLK8 (kallikrein-related peptidase 8) gene as prognostic markers for lung cancer. Methods: Real-time reverse-transcription PCR was used to analyze the mRNAs encoded by KLK8 (particularly 2 mRNA splice variants, KLK8-T3 and KLK8-T4) in 60 non–small-cell lung cancer (NSCLC) tumors and in paired unaffected tissues. The ratios of these mRNAs to those encoded by the KLK5, KLK6, KLK7, KLK10, KLK11, KLK13, and KLK14 genes were also determined and analyzed for correlations with various clinicopathologic variables. Results: KLK8-T3 and KLK8-T4 were the most abundant of the 6 mRNA isoforms identified in lung tissues. The overall expression of the KLK8 gene and the amounts of the KLK8-T3 and KLK8-T4 mRNAs were significantly increased in lung tumor tissue (P < 0.0001). Univariate survival analysis revealed significant relationships of the relative concentrations of mRNA splice variants KLK8 (P = 0.043), KLK8-T3 (P = 0.037), and KLK8-T4 (P = 0.009) with overall survival (OS). Cox multivariate analysis indicated that the amount of KLK8-T4 mRNA was an independent prognostic factor for OS (relative risk = 3.90; P = 0.016) and that high KLK8-T4/KLK7, KLK8-T4/KLK10, and KLK8-T4/KLK11 mRNA ratios in NSCLC indicated increased risk of death. The increase was approximately 5-fold for the KLK8-T4/KLK7 and KLK8-T4/KLK10 ratios (P = 0.006, and P = 0.011, respectively) and 8-fold for the KLK8-T4/KLK11 ratio (P = 0.001). Conclusions: The KLK8-T4 alternative splice variant, alone or in combination, may be a new independent marker of unfavorable prognosis in lung cancer.

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Reid, Janet C., Nigel C. Bennett, Carson R. Stephens, Melanie L. Carroll, Viktor Magdolen, Judith A. Clements und John D. Hooper. „In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B“. Biological Chemistry 397, Nr. 12 (01.12.2016): 1299–305. http://dx.doi.org/10.1515/hsz-2016-0163.

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Abstract Kallikrein-related peptidase (KLK) 14 is a serine protease linked to several pathologies including prostate cancer. We show that KLK14 has biphasic effects in vitro on activating and inhibiting components of the prostate cancer associated hepatocyte growth factor (HGF)/Met system. At 5–10 nm, KLK14 converts pro-HGF to the two-chain heterodimer required for Met activation, while higher concentrations degrade the HGF α-chain. HGF activator-inhibitor (HAI)-1A and HAI-1B, which inhibit pro-HGF activators, are degraded by KLK14 when protease:inhibitor stoichiometry is 1:1 or the protease is in excess. When inhibitors are in excess, KLK14 generates HAI-1A and HAI-1B fragments known to inhibit pro-HGF activating serine proteases. These in vitro data suggest that increased KLK14 activity could contribute at multiple levels to HGF/Met-mediated processes in prostate and other cancers.

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Avgeris, Margaritis, Georgia Papachristopoulou, Athanasios Polychronis und Andreas Scorilas. „Down-regulation of kallikrein-related peptidase 5 (KLK5) expression in breast cancer patients: a biomarker for the differential diagnosis of breast lesions“. Clinical Proteomics 8, Nr. 1 (2011): 5. http://dx.doi.org/10.1186/1559-0275-8-5.

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Weidinger, Stephan, Hansjörg Baurecht, Stefan Wagenpfeil, John Henderson, Natalija Novak, Aileen Sandilands, Huijia Chen et al. „Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk“. Journal of Allergy and Clinical Immunology 122, Nr. 3 (September 2008): 560–68. http://dx.doi.org/10.1016/j.jaci.2008.05.050.

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Brännström, Kristoffer, Anders Öhman, Ulrich von Pawel Rammingen, Anders Olofsson und Maria Brattsand. „Characterization of SPINK9, a KLK5-specific inhibitor expressed in palmo-plantar epidermis“. Biological Chemistry 393, Nr. 5 (01.05.2012): 369–77. http://dx.doi.org/10.1515/hsz-2011-0238.

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Abstract SPINK9, a Kazal-type serine protease inhibitor, is almost exclusively expressed in the palmo-plantar epidermis. SPINK9 selectively inhibits kallikrein-related peptidase 5 (KLK5), no other target enzyme is known at present. In this study, we defined the reactive loop to residues 48 and 49 of SPINK9 and characterized the inhibition and binding of different SPINK9 variants towards KLK5, KLK7, KLK8 and KLK14. Substitutions of single amino acids in the reactive loop had a large impact on both inhibitory efficiency and specificity. Binding studies showed that it is mainly the dissociation rate that is affected by the amino acid substitutions. The inhibitory effect of wild-type SPINK9 was clearly pH-dependent with an improved effect at a pH similar to that of the outer layers of the skin. Modeling of the enzyme-inhibitor complexes showed that the reactive loop of SPINK9 fits very well into the deep negatively charged binding pocket of KLK5. A decrease in pH protonates His48 of the wild-type protein resulting in a positively charged residue, thereby explaining the observed decreased dissociation rate. Interestingly, substitution with a positively charged amino acid at position 48 resulted in a more efficient inhibitor at higher pH.

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Fukushima, Tsuyoshi, Shuichiro Uchiyama, Hiroyuki Tanaka und Hiroaki Kataoka. „Hepatocyte Growth Factor Activator: A Proteinase Linking Tissue Injury with Repair“. International Journal of Molecular Sciences 19, Nr. 11 (01.11.2018): 3435. http://dx.doi.org/10.3390/ijms19113435.

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Hepatocyte growth factor (HGF) promotes pleiotropic signaling through its specific receptor tyrosine kinase, MET. As such, it has important roles in the regeneration of injured tissues. Since HGF is produced mainly by mesenchymal cells and MET is expressed in most epithelial, endothelial and somatic stem cells, HGF functions as a typical paracrine growth factor. HGF is secreted as an inactive precursor (proHGF) and requires proteolytic activation to initiate HGF-induced MET signaling. HGF activator (HGFAC) is a serum activator of proHGF and produces robust HGF activities in injured tissues. HGFAC is a coagulation factor XII-like serine endopeptidase that circulates in the plasma as a zymogen (proHGFAC). Thrombin, kallikrein-related peptidase (KLK)-4 or KLK-5 efficiently activates proHGFAC. The activated HGFAC cleaves proHGF at Arg494-Val495, resulting in the formation of the active disulfide-linked heterodimer HGF. Macrophage stimulating protein, a ligand of RON, is also activated by HGFAC in vivo. Although HGFAC functions primarily at the site of damaged tissue, a recent report has suggested that activated HGFAC relays a signal to stem cells in non-injured tissues via proHGF activation in the stem cell niche. This review focuses on current knowledge regarding HGFAC-mediated proHGF activation and its roles in tissue regeneration and repair.

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Nomura, Hayato, Mutsumi Suganuma, Takuya Takeichi, Michihiro Kono, Yuki Isokane, Ko Sunagawa, Mina Kobashi et al. „Multifaceted Analyses of Epidermal Serine Protease Activity in Patients with Atopic Dermatitis“. International Journal of Molecular Sciences 21, Nr. 3 (30.01.2020): 913. http://dx.doi.org/10.3390/ijms21030913.

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The serine proteases kallikrein-related peptidase (KLK) 5 and KLK7 cleave cell adhesion molecules in the epidermis. Aberrant epidermal serine protease activity is thought to play an important role in the pathogenesis of atopic dermatitis (AD). We collected the stratum corneum (SC) from healthy individuals (n = 46) and AD patients (n = 63) by tape stripping and then measuring the trypsin- and chymotrypsin-like serine protease activity. We also analyzed the p.D386N and p.E420K of SPINK5 variants and loss-of-function mutations of FLG in the AD patients. The serine protease activity in the SC was increased not only in AD lesions but also in non-lesions of AD patients. We found, generally, that there was a positive correlation between the serine protease activity in the SC and the total serum immunoglobulin E (IgE) levels, serum thymus and activation-regulated chemokine (TARC) levels, and peripheral blood eosinophil counts. Moreover, the p.D386N or p.E420K in SPINK5 and FLG mutations were not significantly associated with the SC’s serine protease activity. Epidermal serine protease activity was increased even in non-lesions of AD patients. Such activity was found to correlate with a number of biomarkers of AD. Further investigations of serine proteases might provide new treatments and prophylaxis for AD.

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Ishida, Koichi, Liyue Qin, Ting Wang, Ying Lei, Weiwei Hu, Geng Zhu, Qianqian Zhuang et al. „Local mechanisms for acupoint sensitization in gall bladder meridian of foot shaoyang-a gene chip study“. Acupuncture & Electro-Therapeutics Research 44, Nr. 2 (01.06.2019): 77–87. http://dx.doi.org/10.3727/036012919x15650315071898.

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Acupuncture manipulations are clinically important to traditional Chinese medicine, yet the biological mechanisms have not been fully understood. This study aimed to investigate continuous stimulation-induced gene expression changes at stimulated and non-stimulated adjacent acupoints in the same meridian. Catgut embedding into acupoint (CEP) was conducted at acupoint Yanglingquan (gall bladder meridian of foot-shaoyang 34, GB34) of Sprague Dawley rats once or continuously for eight weeks, and gene expression changes at GB34 were assessed by gene chip array analysis 72 h after the last CEP treatment. A total of 688 genes exhibited opposite changes in expression between the two treatments, and 1,336 genes were regulated only by the eight-week CEP treatment. Ingenuity Pathway Analysis revealed that among these differentially regulated genes by one-time and eight-week CEP treatment, insulin-like growth factor-1 pathway and integrin-linked kinase pathway, and Wnt/~ catenin signaling pathway match the observed gene changes to predicted up/down regulation patterns. Upstream analysis further predicted six molecules, namely, tumor necrosis factor, interleukin 1~, interleukin la, kallikrein-related peptidase 5, protein kinase Ca, and catenin ~1. On the other hand, continuous eight-week CEP stimulation at acupoint Xuanzhong (GB39) caused similar changes in the expression of 32 genes at acupoints GB34 and Fengshi (GB31) on the same meridian. Taken together, our results provide the first molecular evidence for the local acupoints' mechanisms for acupoint sensitization theory, and implicate the existence of signaling pathways, either direct or indirect, between acupoints within the meridian GB.

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Schaap, Mirjam J., Finola M. Bruins, Xuehui He, Kadri Orro, Malou Peppelman, Piet E. J. van Erp, Elke M. G. J. de Jong, Hans J. P. M. Koenen, Ellen H. van den Bogaard und Marieke M. B. Seyger. „Skin Surface Protein Detection by Transdermal Analysis Patches in Pediatric Psoriasis“. Skin Pharmacology and Physiology 34, Nr. 5 (2021): 271–80. http://dx.doi.org/10.1159/000516110.

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Introduction: Transdermal analysis patches (TAPs) noninvasively measure soluble proteins in the stratum corneum. Ultimately, such local protein profiles could benefit the search for biomarkers to improve personalized treatment in psoriasis. This study aimed to explore the patient friendliness and protein detection by TAP in pediatric psoriasis in daily clinical practice. Methods: In this observational study, TAPs measuring CXC chemokine ligand (CXCL)-1/2, CC chemokine ligand (CCL)-27, interleukin (IL)-1RA, IL-23, IL-1α, IL-8, IL-4, IL-22, IL-17A, vascular endothelial growth factor (VEGF), human beta-defensin (hBD)-2, hBD-1, and kallikrein-related peptidase (KLK)-5 were applied on lesional, peri-lesional, and non-lesional skin sites of psoriasis patients aged >5 to <18 years. Discomfort during TAP removal as an indicator for patient friendliness was assessed by visual analogue scale (VAS; range 0–10). Results: Thirty-two patients (median age 14.0 years) were included, of which 19 were treated with solely topical agents and 13 with systemic treatment. The median VAS of discomfort during TAP removal was 1.0 (interquartile range 1.0). Significantly higher levels in lesional versus non-lesional skin were found for IL-1RA, VEGF, CXCL-1/2, hBD-2, and IL-8, whereas lower levels were found for IL-1α. Skin surface proteins were measured in both treatment groups, with significant higher lesional levels of KLK-5, IL-1RA, hBD-2, IL-1α, IL-23, and CCL-27 in the systemic treatment group. Conclusion: The TAP platform holds the potential for patient-friendly and noninvasive monitoring of skin-derived proteins in pediatric psoriasis patients in daily clinical practice.

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Beaufort, Nathalie, Karolina Plaza, Daniel Utzschneider, Amelie Schwarz, Julia M. Burkhart, Sabine Creutzburg, Mekdes Debela, Manfred Schmitt, Christian Ries und Viktor Magdolen. „Interdependence of kallikrein-related peptidases in proteolytic networks“. Biological Chemistry 391, Nr. 5 (01.05.2010): 581–87. http://dx.doi.org/10.1515/bc.2010.055.

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Abstract Human kallikrein-related peptidases (KLKs) are 15 homologous serine proteases involved in several (patho)physiological processes, including cancer. Secreted as precursors, they are activated upon proteolytic release of a short pro-peptide. We searched for interconnection of KLKs within extracellular proteolytic networks leading to activation of protease zymogens and found that (i) pro-KLK activation by other KLKs is scarce, with the exception of pro-KLK11, which is efficiently activated by KLK4 and 5; (ii) pro-KLK4 is activated by matrix metalloproteinase 3; and (iii) trypsin-like KLKs efficiently activate the serine protease urokinase. Our observations provide new insights into the regulation of these important tumor-associated proteases.

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Jung, Monika, Annika Schaefer, Isabel Steiner, Carsten Kempkensteffen, Carsten Stephan, Andreas Erbersdobler und Klaus Jung. „Robust MicroRNA Stability in Degraded RNA Preparations from Human Tissue and Cell Samples“. Clinical Chemistry 56, Nr. 6 (01.06.2010): 998–1006. http://dx.doi.org/10.1373/clinchem.2009.141580.

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Abstract Background: RNA integrity is the essential factor that determines the accuracy of mRNA transcript measurements obtained with quantitative real-time reverse-transcription PCR (RT-qPCR), but evidence is clearly lacking on whether this conclusion also applies to microRNAs (miRNAs). We evaluated this issue by comparative analysis of the dependence of miRNA and mRNA measurements on RNA integrity in renal and prostate samples, under both model and clinical conditions. Methods: Samples of total RNA isolated from human renal tissue and Caki-2 cells, as well as from prostate tissue and LNCaP cells, were incubated at 80 °C for 5–240 min. We subsequently determined the RNA integrity number (RIN) and used RT-qPCR to measure various miRNAs (miR-141, miR-155, miR-200c, and miR-210 in renal samples, and miR-96, miR-130b, miR-149, miR-205, and miR-222 in prostate samples). We similarly measured mRNAs encoded by CDH16 (cadherin 16, KSP-cadherin), PPIA [peptidylprolyl isomerase A (cycophilin A)], and TBP (TATA box binding protein) in renal samples, and HIF1A [hypoxia-inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor)], HPRT1 (hypoxanthine phosphoribosyltransferase 1), and KLK3 (kallikrein-related peptidase 3; also known as PSA) in prostate samples. Additionally, we quantified selected miRNAs and mRNAs in samples of RNAs with different RIN values that we isolated from clinical samples. The effect of RIN on the miRNA and mRNA data was assessed by linear regression analysis and group comparison. Results: The heat-incubation experiments of cell line and tissue RNAs showed that RIN values had negligible or no effect on miRNA results, whereas all mRNAs gradually decreased with decreasing RIN values. These findings were corroborated by our findings with clinical samples. Conclusions: Our results suggest the stability of miRNAs to be generally robust, which makes feasible accurate miRNA measurements with RT-qPCR, even in degraded RNA preparations for which reliable mRNA analyses are commonly inapplicable.

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Pathak, Monika, Szu Shen Wong, Ingrid Dreveny und Jonas Emsley. „Structure of plasma and tissue kallikreins“. Thrombosis and Haemostasis 110, Nr. 09 (2013): 423–33. http://dx.doi.org/10.1160/th12-11-0840.

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SummaryThe kallikrein kinin system (KKS) consists of serine proteases involved in the production of peptides called kinins, principally bradykinin and Lys-bradykinin (kallidin). The KKS contributes to a variety of physiological processes including inflammation, blood pressure control and coagulation. Here we review the protein structural data available for these serine proteases and examine the molecular mechanisms of zymogen activation and substrate recognition focusing on plasma kallikrein (PK) and tissue kallikrein (KLK1) cleavage of kininogens. PK circulates as a zymogen bound to high-molecular-weight kininogen (HK). PK is activated by coagulation factor XIIa and then cleaves HK to generate bradykinin and factor XII to generate further XIIa. A structure has been described for the activated PK protease domain in complex with the inhibitor benzamidine. Kallikrein-related peptidases (KLKs) have a distinct domain structure and exist as a family of 15 genes which are differentially expressed in many tissues and the central nervous system. They cleave a wide variety of substrates including low-molecular-weight kininogen (LK) and matrix proteins. Crystal structures are available for KLK1, 3, 4, 5, 6 and 7 activated protease domains typically in complex with S1 pocket inhibitors. A substrate mimetic complex is described for KLK3 which provides insight into substrate recognition. A zymogen crystal structure determined for KLK6 reveals a closed S1 pocket and a novel mechanism of zymogen activation. Overall these structures have proved highly informative in understanding the molecular mechanisms of the KKS and provide templates to design inhibitors for treatment of a variety of diseases.

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Chee, Jessica, Jasmine Singh, Anupam Naran, Neil L. Misso, Philip J. Thompson und Kanti D. Bhoola. „Novel expression of kallikreins, kallikrein-related peptidases and kinin receptors in human pleural mesothelioma“. Biological Chemistry 388, Nr. 11 (01.11.2007): 1235–42. http://dx.doi.org/10.1515/bc.2007.139.

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Abstract Malignant mesothelioma is an aggressive cancer of the pleura that is causally related to exposure to asbestos fibres. The kallikrein serine proteases [tissue (hK1) and plasma (hKB1) kallikreins, and kallikrein-related peptidases (KRP/hK2–15)] and the mitogenic kinin peptides may have a role in tumourigenesis. However, it is not known whether hK1, hKB1, KRP/hK proteins or kinin receptors are expressed in pleural mesotheliomas. The expression of hK1, hKB1, KRP/hK2, 5, 6, 7, 8 and 9, and kinin B1 and B2 receptors was assessed in archived selected normal tissue and mesothelioma tumour sections by immunoperoxidase and immunofluorescence labelling. hK1, hKB1 and kinin B1 and B2 receptors were expressed in malignant cells of the epithelioid and sarcomatoid components of biphasic mesothelioma tumour cells. The percentage of cells with cytoplasmic and nuclear labelling and the intensity of labelling were similar for hK1, hKB1 and the kinin receptors. KRP/hK2, 6, 8 and 9 were also expressed in the cytoplasm and nuclei of mesothelioma cells, whereas KRP/hK5 and hK7 showed predominantly cytoplasmic localisation. This is a first report, but further studies are required to determine whether these proteins have a functional role in the pathogenesis of mesothelioma and/or may be potential biomarkers for pleural mesothelioma.

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Sarwar, Md Shahid, Christina N. Ramirez, Hsiao-Chen Dina Kuo, Pochung Chou, Renyi Wu, Davit Sargsyan, Ahmad Shannar et al. „Abstract 5266: Metabolic rewiring and epigenetic reprogramming by the environmental carcinogen benzo[a]pyrene in a two-stage skin carcinogenesis mouse model and cancer interception by triterpenoid ursolic acid“. Cancer Research 83, Nr. 7_Supplement (04.04.2023): 5266. http://dx.doi.org/10.1158/1538-7445.am2023-5266.

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Abstract Nonmelanoma skin cancer (NMSC) is the most common skin cancer burden on the U.S. population. Environmental exposure to chemical carcinogens is one of the major causes of NMSC initiation, promotion, and progression. Ursolic acid (UA) is a naturally abundant pentacyclic triterpenoid showing anticancer potentials against diverse cancers. In the current study, we developed a two-stage skin carcinogenesis model in SKH1 hairless mice by administering cancer-initiating agent benzo[a]pyrene (B[a]P) and promoting agent 12-O-tetra-decanoylphorbol-13-acetate to study the epigenetic, transcriptomic, and metabolic changes at different stages (5, 20, and 26 weeks) during the development of NMSC, and investigated how UA regulates B[a]P-mediated alterations for NMSC interception. We found that UA protects against B[a]P-induced tumorigenesis at different phases of NMSC. Epigenetic CpG methyl-seq showed UA abrogated B[a]P-mediated alterations in differentially methylated regions (DMRs) profiles. Transcriptomic RNA-seq data exhibited UA reversed the differentially expressed genes (DEGs) of several inflammatory genes, such as chemokine ligand 8 (Ccl8) and interleukin 17F (Il17f), and epigenetic genes, such as DNA-methyltransferase 3-like (Dnmt3l) and protein-l-isoaspartate O-methyltransferase domain-containing protein 1 (Pcmtd1) during different stages of NMSC. Association study between DEGs and DMRs showed that B[a]P promoted transcription of kallikrein-related peptidase 13 (Klk13) by promoter demethylation, while UA suppressed Klk13 expression through hypermethylation in the promoter during the initiation stage, indicating the early intervention of UA. Ingenuity pathway analysis further showed significant upregulation of macrophage-stimulating protein-recepteur d'origine nantais (MSP-RON) signaling pathway by B[a]P during the initiation stage while suppressed by UA treatment. The metabolomic study revealed UA modulated cancer-associated changes in metabolisms, including the TCA cycle and pyruvate metabolism/metabolites during the promotion phase, indicating UA plays a critical role in regulating B[a]P-regulated metabolic changes and intercepting NMSC progression. In summary, UA protects against the environmental carcinogen B[a]P-driven epigenetic, transcriptomic, and metabolic changes during the initiation, promotion, and progression of NMSC, potentially contributing to the anticancer effects of UA. (Supported by NIH R01 CA200129 to A.N.K) Citation Format: Md. Shahid Sarwar, Christina N. Ramirez, Hsiao-Chen Dina Kuo, Pochung Chou, Renyi Wu, Davit Sargsyan, Ahmad Shannar, Rebecca Mary Peter, Ran Yin, Yujue Wang, Xiaoyang Su, Ah-Ng Kong. Metabolic rewiring and epigenetic reprogramming by the environmental carcinogen benzo[a]pyrene in a two-stage skin carcinogenesis mouse model and cancer interception by triterpenoid ursolic acid. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5266.

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Hamilton, Brian S., und Gary R. Whittaker. „Cleavage Activation of Human-adapted Influenza Virus Subtypes by Kallikrein-related Peptidases 5 and 12“. Journal of Biological Chemistry 288, Nr. 24 (23.04.2013): 17399–407. http://dx.doi.org/10.1074/jbc.m112.440362.

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Wang, Ping, Viktor Magdolen, Christof Seidl, Julia Dorn, Enken Drecoll, Matthias Kotzsch, Feng Yang et al. „Kallikrein-related peptidases 4, 5, 6 and 7 regulate tumour-associated factors in serous ovarian cancer“. British Journal of Cancer 119, Nr. 7 (Oktober 2018): 1–9. http://dx.doi.org/10.1038/s41416-018-0260-1.

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Keuylian, Zela, und Alain Hovnanian. „Mechanistic insight from murine models of Netherton syndrome“. Biological Chemistry 397, Nr. 12 (01.12.2016): 1223–28. http://dx.doi.org/10.1515/hsz-2016-0203.

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Abstract Protease regulation plays a crucial role in skin homeostasis and inflammation as revealed by the identification of loss-of-function mutations in SPINK5 (serine protease inhibitor of Kazal type 5) in Netherton sydrome (NS). SPINK5 encodes LEKTI (lympho-epithelial Kazal type related inhibitor), a multidomain serine protease inhibitor expressed in all stratified epithelia. Our laboratory has developed a number of murine models which have been instrumental in dissecting the pathogenesis of NS. This minireview discusses the major findings of these models and emphasizes the role of protease regulation, especially kallikrein-related peptidases in NS.

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Olkhov, E., T. H. Van Der Kwast, K. Kron, V. Pethe, H. Ozcelik, L. Briollais, N. E. Fleshner, E. P. Diamandis, A. R. Zlotta und B. Bapat. „543 Methylation of Kallikrein-related peptidases as novel diagnostic and prognostic biomarkers for prostate cancer“. European Urology Supplements 11, Nr. 1 (Februar 2012): e543-e543a. http://dx.doi.org/10.1016/s1569-9056(12)60540-5.

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Ehrenfeld, Pamela, Carlos D. Figueroa, Luis Molina, Tania Koning, Myriam Velasco, Felipe A. Bustamante-Barrientos und Alexander Ortloff. „Expression and Distribution of Kallikrein-related Peptidases 5, 7, 8 and 10 in Normal Apocrine Gland of Canine Skin“. International Journal of Morphology 41, Nr. 1 (Februar 2023): 210–15. http://dx.doi.org/10.4067/s0717-95022023000100210.

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Shahinian, Hasmik, Daniela Loessner, Martin L. Biniossek, Jayachandran N. Kizhakkedathu, Judith A. Clements, Viktor Magdolen und Oliver Schilling. „Secretome and degradome profiling shows that Kallikrein-related peptidases 4, 5, 6, and 7 induce TGFβ-1 signaling in ovarian cancer cells“. Molecular Oncology 8, Nr. 1 (01.10.2013): 68–82. http://dx.doi.org/10.1016/j.molonc.2013.09.003.

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Jendrny, Cathleen, und Annette G. Beck-Sickinger. „Inhibition of Kallikrein-Related Peptidases 7 and 5 by Grafting Serpin Reactive-Center Loop Sequences onto Sunflower Trypsin Inhibitor-1 (SFTI-1)“. ChemBioChem 17, Nr. 8 (22.12.2015): 719–26. http://dx.doi.org/10.1002/cbic.201500539.

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Barabe, J., D. Huberdeau und A. Bernoussi. „Influence of sodium balance on urinary excretion of immunoreactive kinins in rats“. American Journal of Physiology-Renal Physiology 254, Nr. 4 (01.04.1988): F484—F491. http://dx.doi.org/10.1152/ajprenal.1988.254.4.f484.

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Antibodies against bradykinin (BK) and its metabolites, namely des-Arg9-BK and des-Phe8,Arg9-BK were raised in rabbits, and specific radioimmunoassays (RIA) for these peptides were developed. Specificity studies showed that each RIA was specific for its antigen, since the cross-reactivities of various kinin-related peptides were less than 1.5%. The lowest concentration of peptide that could be measured in these assays was approximately 60 pg/ml. The antibodies were used to measure concentrations of BK and its metabolites in urine and kidneys of rats maintained on different sodium balance for 5 wk. The results showed that normal rats excrete low quantities of BK (63.78 +/- 2.98 ng/day, 88 determinations). The urinary excretion of des-Arg9-BK averaged 77.69 +/- 5.53 ng/day, whereas the amount of des-Phe8,Arg9-BK is equal to 7.13 +/- 0.42 ng/day. Sodium loading brings about a small decrease in the concentration of BK (45.57 +/- 2.36 ng/day, 76 determinations), whereas sodium depletion significantly increased the excretion of BK (94.23 +/- 5.50, 102 determinations, P less than 0.01) accompanied by no modification of the excretion of metabolites. Regression analysis of the results showed a positive correlation between urinary volume and BK in control and sodium-loaded animals and urinary BK and sodium in the sodium-loaded group. In kidney homogenates, sodium depletion increased not only the concentration of BK (10-fold) but also that of des-Arg9-BK and des-Phe8,Arg9-BK by a factor of four and two, respectively, when compared with normal and sodium-loaded animals. These results support the hypothesis that the renal kallikrein-kinin system may be regulated by corticosteroids.

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Thomadaki, Hellinida, Konstantinos Mavridis, Maroulio Talieri und Andreas Scorilas. „Treatment of PC3 prostate cancer cells with mitoxantrone, etoposide, doxorubicin and carboplatin induces distinct alterations in the expression of kallikreins 5 and 11“. Thrombosis and Haemostasis 101, Nr. 02 (2009): 373–80. http://dx.doi.org/10.1160/th08-01-0025.

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SummarySeveral of the novel kallikrein-related peptidases (tissue kallikreins; KLKs) are emerging new serum and/or tissue biomarkers for prostate cancer (CaP) diagnosis, prognosis and monitoring. In the present research approach, our objective was to investigate the possible alterations in the mRNA expression levels of KLK5 and KLK11 genes in prostate cancer cells PC3 as a response to treatment with Mitoxantrone, Etoposide, Doxorubicin and Carboplatin. Viability was assessed with the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay after cell treatment with either mitoxantrone (2 μM), etoposide (20 μM), doxorubicin (1 μM), or carboplatin (15 μM), for 24, 48 and 72 hours. Additionally, trypan blue staining revealed that in PC3 cells all drugs displayed almost the same limited necrotic effects which appeared mainly at 72 hours of treatment. PC3 prostate cancer cells showed a concentration- and time-dependent increased cytotoxicity to the drugs under study which was mainly due to reduction of cell proliferation efficiency. Distinct modulations of KLK5 and KLK11 genes, at the mRNA level, were observed, supporting a drug-dependent cell response. Our experimental data demonstrate that the molecular profile mainly of KLK5 gene may serve as a new potential molecular biomarker predicting treatment response in CaP cells.

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Jendrny, Cathleen, und Annette G. Beck-Sickinger. „Inside Back Cover: Inhibition of Kallikrein-Related Peptidases 7 and 5 by Grafting Serpin Reactive-Center Loop Sequences onto Sunflower Trypsin Inhibitor-1 (SFTI-1) (ChemBioChem 8/2016)“. ChemBioChem 17, Nr. 8 (05.04.2016): 784. http://dx.doi.org/10.1002/cbic.201600146.

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Chavakis, Triantafyllos, Sandip M. Kanse, Florea Lupu, Hans-Peter Hammes, Werner Müller-Esterl, Robin A. Pixley, Robert W. Colman und Klaus T. Preissner. „Different mechanisms define the antiadhesive function of high molecular weight kininogen in integrin- and urokinase receptor–dependent interactions“. Blood 96, Nr. 2 (15.07.2000): 514–22. http://dx.doi.org/10.1182/blood.v96.2.514.

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Abstract Proteolytic cleavage of single-chain high molecular weight kininogen (HK) by kallikrein releases the short-lived vasodilator bradykinin and leaves behind 2-chain high molecular weight kininogen (HKa) that has been previously reported to exert antiadhesive properties as well as to bind to the urokinase receptor (uPAR) on endothelial cells. In this study we defined the molecular mechanisms for the antiadhesive effects of HKa related to disruption of integrin- and uPAR-mediated cellular interactions. Vitronectin (VN) but not fibrinogen or fibronectin-dependent vβ3 integrin–mediated adhesion of endothelial cells was blocked by HKa or its isolated domain 5. In a purified system, HKa but not HK competed for the interaction of VN with vβ3 integrin, because HKa and the isolated domain 5 but not HK bound to both multimeric and native VN in a Zn2+-dependent manner. The interaction between HKa or domain 5 with VN was prevented by heparin, plasminogen activator inhibitor-1, and a recombinant glutathione-S-transferase (GST)-fusion peptide GST-VN (1-77) consisting of the amino terminal portion of VN (amino acids 1-77), but not by a cyclic arginyl-glycyl-aspartyl peptide, indicating that HKa interacts with the amino terminal portion of VN (“somatomedin B region”). Furthermore, we have confirmed that HKa but not HK bound to uPAR and to the truncated 2-domain form of uPAR lacking domain 1 in a Zn2+-dependent manner. Through these interactions, HKa or its recombinant His-Gly-Lys–rich domain 5 completely inhibited the uPAR-dependent adhesion of myelomonocytic U937 cells and uPAR-transfected BAF-3 cells to VN and thereby promoted cell detachment. By immunogold electron microscopy, both VN and HK/HKa were found to be colocalized in sections from human atherosclerotic coronary artery, indicating that the described interactions are likely to take place in vivo. Taken together, HK and HKa inhibit different VN-responsive adhesion receptor systems and may thereby influence endothelial cell- or leukocyte-related interactions in the vasculature, particularly under inflammatory conditions.

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Chavakis, Triantafyllos, Sandip M. Kanse, Florea Lupu, Hans-Peter Hammes, Werner Müller-Esterl, Robin A. Pixley, Robert W. Colman und Klaus T. Preissner. „Different mechanisms define the antiadhesive function of high molecular weight kininogen in integrin- and urokinase receptor–dependent interactions“. Blood 96, Nr. 2 (15.07.2000): 514–22. http://dx.doi.org/10.1182/blood.v96.2.514.014k45_514_522.

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Proteolytic cleavage of single-chain high molecular weight kininogen (HK) by kallikrein releases the short-lived vasodilator bradykinin and leaves behind 2-chain high molecular weight kininogen (HKa) that has been previously reported to exert antiadhesive properties as well as to bind to the urokinase receptor (uPAR) on endothelial cells. In this study we defined the molecular mechanisms for the antiadhesive effects of HKa related to disruption of integrin- and uPAR-mediated cellular interactions. Vitronectin (VN) but not fibrinogen or fibronectin-dependent vβ3 integrin–mediated adhesion of endothelial cells was blocked by HKa or its isolated domain 5. In a purified system, HKa but not HK competed for the interaction of VN with vβ3 integrin, because HKa and the isolated domain 5 but not HK bound to both multimeric and native VN in a Zn2+-dependent manner. The interaction between HKa or domain 5 with VN was prevented by heparin, plasminogen activator inhibitor-1, and a recombinant glutathione-S-transferase (GST)-fusion peptide GST-VN (1-77) consisting of the amino terminal portion of VN (amino acids 1-77), but not by a cyclic arginyl-glycyl-aspartyl peptide, indicating that HKa interacts with the amino terminal portion of VN (“somatomedin B region”). Furthermore, we have confirmed that HKa but not HK bound to uPAR and to the truncated 2-domain form of uPAR lacking domain 1 in a Zn2+-dependent manner. Through these interactions, HKa or its recombinant His-Gly-Lys–rich domain 5 completely inhibited the uPAR-dependent adhesion of myelomonocytic U937 cells and uPAR-transfected BAF-3 cells to VN and thereby promoted cell detachment. By immunogold electron microscopy, both VN and HK/HKa were found to be colocalized in sections from human atherosclerotic coronary artery, indicating that the described interactions are likely to take place in vivo. Taken together, HK and HKa inhibit different VN-responsive adhesion receptor systems and may thereby influence endothelial cell- or leukocyte-related interactions in the vasculature, particularly under inflammatory conditions.

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Luo, Yanmin, Premlata Kumar und Carole R. Mendelson. „Estrogen-Related Receptor γ (ERRγ) Regulates Oxygen-Dependent Expression of Voltage-gated Potassium (K+) Channels and Tissue Kallikrein during Human Trophoblast Differentiation“. Molecular Endocrinology 27, Nr. 6 (01.06.2013): 940–52. http://dx.doi.org/10.1210/me.2013-1038.

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Abstract Estrogen-related receptor γ (ERRγ) serves a critical O2-dependent regulatory role in the differentiation of human cytotrophoblasts to syncytiotrophoblast. In this study, we investigated expression of genes encoding tissue kallikrein (KLK1) and voltage-gated K+ channels (KV7) during differentiation of human trophoblasts in culture and the roles of ERRγ and O2 tension in their regulation. Expression of KLK1 and the KV7 channel subunits, KCNQ1, KCNE1, KCNE3, and KCNE5, increased during differentiation of cultured human trophoblast cells in a 20% O2 environment. Notably, together with ERRγ, expression of KLK1, KCNQ1, KCNE1, KCNE3, and KCNE5 was markedly reduced when cells were cultured in a hypoxic environment (2% O2). Moreover, upon transduction of trophoblast cells with short hairpin RNAs for endogenous ERRγ, KLK1, KCNQ1, KCNE1, and KCNE3 expression was significantly decreased. Promoter and site-directed mutagenesis studies in transfected cells identified putative ERRγ response elements within the KLK1 and KCNE1 5′-flanking regions required for ERRγ-stimulated transcriptional activity. Binding of endogenous ERRγ to these ERRγ response elements increased during trophoblast differentiation in culture and was inhibited by hypoxia. The KV7 blocker linopirdine reduced human chorionic gonadotropin secretion and aggregation of cultured human trophoblasts, suggesting a possible role of KV7 channels in cell fusion and differentiation. Illumina gene expression arrays of cultured human trophoblast cells revealed several genes upregulated during syncytiotrophoblast differentiation and downregulated upon ERRγ knockdown involved in cell differentiation, adhesion, and synthesis of steroid and peptide hormones required for placental development and function. Collectively, these findings suggest that ERRγ mediates O2-dependent expression of genes involved in human trophoblast differentiation, function, and vascular homeostasis.

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Bandiera, Elisabetta, Laura Zanotti, Eliana Bignotti, Chiara Romani, Renata Tassi, Paola Todeschini, Germana Tognon et al. „Human Kallikrein 5: An Interesting Novel Biomarker in Ovarian Cancer Patients that Elicits a Humoral Response“. International Journal of Biological Markers 24, Nr. 3 (Juli 2009): 211. http://dx.doi.org/10.1177/172460080902400337.

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Background and aim Epithelial ovarian cancer (EOC) is characterized by few early symptoms, presentation at an advanced stage and poor survival. As a result, it is the most frequent cause of death from gynecological cancer. Recently, not only tumor antigens but also antibodies produced in response to the disease have been considered as biomarkers for early detection of EOC. Kallikrein-related peptidases (KLK) are secreted serine proteases implicated in tumor progression. A recent study has demonstrated that the serum KLK5 (sKLK5) concentration is elevated in patients with EOC, but the existence of a humoral immune response to KLK5 has not been studied. Moreover, the presence of sKLK5 in other ovarian diseases has not been clearly determined. The aim of this study was to examine the serological existence of anti-KLK5 antibodies, bound to KLK5 into circulating immune complexes (KLK5-lgM and KLK5-lgG ICs) or free antibodies (IgM and IgG), in healthy women and in patients with benign ovarian masses, borderline tumors and EOC. In the same patients we also assessed the levels of sKLK5. Materials and methods Serum samples were obtained from 50 healthy women, 50 patients with benign ovarian masses, 1 7 patients with borderline ovarian tumors, and 50 patients with EOC, before any surgical or chemotherapeutic treatment. Patients with a past or concomitant history of malignancy were excluded from the study. KLK5-lgM and KLK5-lgG ICs were detected with a sandwich ELISA using a polyclonal anti-KLK5 antibody (R&D Systems, Minneapolis, MN, USA) in capture and an anti-hlgM-HRP antibody (Sigma Aldrich Inc, St Louis, MO, USA) or anti-hlgG-HRP antibody (Sigma) in detection. Free anti-KLK5 IgM and IgG were detected with an indirect ELISA using recombinant human kallikrein 5 (R&D) in coating and anti-hlgM-HRP or anti-hlgG-HRP antibodies in detection. Finally, sKLK5 was detected with a sandwich ELISA, using a polyclonal anti-KLK5 antibody in capture and a biotinylated poyclonal anti-hK5 antibody (R&D) in detection. Results Elevated levels of KLK5-lgM and KLK5-lgG ICs were detected in 11% of patients with borderline tumors and 8% of patients with EOC, whereas elevated levels of free anti-KLK5 IgM and IgG were found in 1 7% of patients with borderline tumors and 8% of patients with EOC, resulting in a 100% specificity both in healthy women and patients with benign ovarian disease. Patients with EOC showed higher levels of sKLK5, whereas the protein was almost undetectable in women with other ovarian tumors (Kruskal-Wallis test: p<0.001). In particular, at 95% specificity in healthy controls, 52% of patients with EOC showed high sKLK5 levels. Interestingly, both the immune complexes and the free antibodies were elevated in patients with undetectable sKLK5 levels and borderline tumors with intraepithelial carcinoma. Conclusion Our results showed that sKLK5 is a potential new biomarker to be used in combination with other biomarkers for EOC detection. Moreover, the combination of sKLK5 and antibodies reactive to KLK5 might improve the sensitivity in EOC detection since these antibodies may be found in patients without detectable sKLK5 levels. In conclusion, the identification of an immune response that generally precedes the presence of high levels of circulating antigens may represent a novel useful tool for early EOC detection.

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Dong, Y., L. T. Bui, D. M. Odorico, O. L. Tan, S. A. Myers, H. Samaratunga, R. A. Gardiner und J. A. Clements. „Compartmentalized expression of kallikrein 4 (KLK4/hK4) isoforms in prostate cancer: nuclear, cytoplasmic and secreted forms“. Endocrine-Related Cancer 12, Nr. 4 (Dezember 2005): 875–89. http://dx.doi.org/10.1677/erc.1.01062.

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The prostate-specific antigen-related serine protease gene, kallikrein 4 (KLK4), is expressed in the prostate and, more importantly, overexpressed in prostate cancer. Several KLK4 mRNA splice variants have been reported, but it is still not clear which of these is most relevant to prostate cancer. Here we report that, in addition to the full-length KLK4 (KLK4-254) transcript, the exon 1 deleted KLK4 transcripts, in particular, the 5′-truncated KLK4-205 transcript, is expressed in prostate cancer. Using V5/His6 and green fluorescent protein (GFP) carboxy terminal tagged expression constructs and immunocytochemical approaches, we found that hK4-254 is cytoplasmically localized, while the N-terminal truncated hK4-205 is in the nucleus of transfected PC-3 prostate cancer cells. At the protein level, using anti-hK4 peptide antibodies specific to different regions of hK4-254 (N-terminal and C-terminal), we also demonstrated that endogenous hK4-254 (detected with the N-terminal antibody) is more intensely stained in malignant cells than in benign prostate cells, and is secreted into seminal fluid. In contrast, for the endogenous nuclear-localized N-terminal truncated hK4-205 form, there was less difference in staining intensity between benign and cancer glands. Thus, KLK4-254/hK4-254 may have utility as an immunohistochemical marker for prostate cancer. Our studies also indicate that the expression levels of the truncated KLK4 transcripts, but not KLK4-254, are regulated by androgens in LNCaP cells. Thus, these data demonstrate that there are two major isoforms of hK4 (KLK4-254/hK4-254 and KLK4-205/hK4-205) expressed in prostate cancer with different regulatory and expression profiles that imply both secreted and novel nuclear roles.

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