DOCSLIB.ORG

New Insights Into the Functional Mechanisms and Clinical Applications of the Kallikrein-Related Peptidase Family

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
New Insights Into the Functional Mechanisms and Clinical Applications of the Kallikrein-Related Peptidase Family MOLECULAR ONCOLOGY 1 (2007) 269–287 available at www.sciencedirect.com www.elsevier.com/locate/molonc Review New insights into the functional mechanisms and clinical applications of the kallikrein-related peptidase family Nashmil Emamia,b, Eleftherios P. Diamandisa,b,* aDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1L5, Canada bDepartment of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada ABSTRACT ARTICLE INFO Article history: The Kallikrein-related peptidase (KLK) family consists of fifteen conserved serine proteases Received 13 July 2007 that form the largest contiguous cluster of proteases in the human genome. While primar- Received in revised form ily recognized for their clinical utilities as potential disease biomarkers, new compelling 4 September 2007 evidence suggests that this family plays a significant role in various physiological pro- Accepted 7 September 2007 cesses, including skin desquamation, semen liquefaction, neural plasticity, and body fluid Available online 15 September 2007 homeostasis. KLK activation is believed to be mediated through highly organized proteo- lytic cascades, regulated through a series of feedback loops, inhibitors, auto-degradation Keywords: and internal cleavages. Gene expression is mainly hormone-dependent, even though tran- Kallikrein-related peptidases scriptional epigenetic regulation has also been reported. These regulatory mechanisms are PSA integrated with various signaling pathways to mediate multiple functions. Dysregulation of Proteolytic cascades these pathways has been implicated in a large number of neoplastic and non-neoplastic Skin desquamation pathological conditions. This review highlights our current knowledge of structural/ * Corresponding author. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada. Tel.: þ1 416 586 8443; fax: þ1 416 619 5521. E-mail address: [email protected] (E.P. Diamandis). Abbreviations: ACC, 7-amino-4-carbamoylmethylcoumarin; ACT, anti-chymotrypsin; AD, Alzheimer’s disease; ADAMTS8, ADAM met- allopeptidase with thrombospondin type 1 motif 8; ANF, atrial natriuretic factor; AI, amelogenesis imperfecta; AP, anti plasmin; APMSF, 4-amidino-phenyl-methane-sulfonyl fluoride; AT, antitrypsin; bFGF, basic fibroblast growth factor; B2R, human bradykinin B2 receptor; CAG, cancer-associated gene; cdk, cyclin-dependent kinase 7; CDSN, corneodesmosin; CNS, central nervous system; DSC, desmocollin; DSG, desmoglein; ECM, extracellular matrix; FN, fibronectin; FTD, frontotemporal dementia; FRET, fluorescence resonance energy trans- fer; HEK, human embryonic kidney; hCAP, human cathelicidin; hGH, human growth hormone; HRE, hormone response element; hsp, heat shock protein; IGF, insulin-like growth factor; IGFBP, IGF binding protein; IFN, interferon; IL, interleukin; KD, kallidin; KLK, kalli- krein-related peptidase; KNRK, Kirsten virus-transformed normal rat kidney; LEKTI, lympho-epithelial Kazal-type inhibitor; LLP, low density lipoprotein; LK, low molecular weight kininogen; LMW, low molecular weight; LTP, long-term potentiation; MAPK, mitogen- activated protein kinase; MBP, myelin basic protein; MMP, matrix metalloproteinase; NS, Netherton syndrome; OLG, oligodendrocyte; PAI, plasminogen activator inhibitor; PAP, poly A polymerase; PAR, protease activated receptor; PCI, protein C inhibitor; PI, protease in- hibitor; PKA, protein kinase A; PKC, protein kinase C; PS-SCL, positional scanning synthetic combinatorial library; PTHrp, parathyroid hormone-related peptide; SC, stratum corneum; Sg, seminogelin; siRNA, small interfering RNA; SLPI, secretory leukocyte protease inhib- itor; SNP, single nucleotide polymorphism; SPINK, serine protease inhibitor Kazal-1; TGF, tumour growth factor; uPA, urokinase plas- minogen activator; uPAR, urokinase plasminogen activator receptor; UTR, untranslated region; VEGF, vascular endothelial growth factor; VIP, vasoactive intestinal peptide. 1574-7891/$ – see front matter ª 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.molonc.2007.09.003 270 MOLECULAR ONCOLOGY 1 (2007) 269–287 Semen liquefaction phylogenetic features, functional role and regulatory/signaling mechanisms of this impor- Tumour growth tant family of enzymes. Tumour invasion ª 2007 Federation of European Biochemical Societies. Angiogenesis Published by Elsevier B.V. All rights reserved. uPA signaling PARs 1. Introduction the genes. Some of the common features shared among KLKs include exon/intron organization, number and length Proteases (also known as peptidases) are a major group of en- of exonic regions, intron phase, and conserved translational zymes participating in multitude of physiological processes, start and stop sites, as well as the catalytic triad codons including coagulation, apoptosis, tissue remodeling, and im- (Borgono et al., 2004; Yousef and Diamandis, 2001). Each mune responses (Barrett et al., 2004). Depending on the cleav- geneconsistsof5codingexons,separatedby4introns age site, proteases are classified as exo- and endo-peptidases with the highly conserved GT-AG splice junction pattern. (Barrett et al., 2004). Endopeptidases (or proteinases) cleave Furthermore, with the exception of the ‘‘classic’’ KLKsthat their target proteins internally, whereas exopeptidases se- lack 50 untranslated exons, KLKs contain both 50 and 30 quentially remove amino acids from either the N or C-termi- UTRs. The 30 UTR contains either the canonical (AATAAA) nus (Barrett et al., 2004). Based on the amino acid residue or a variant polyadenylation site distal to the stop codon present at the active site, endopeptidases can further be (Fig. 1)(Borgono et al., 2004). grouped into four major classes of serine-, cysteine-, KLK proteins are secreted serine endoproteases, expressed aspartic-, and metallo-proteinases (Barrett et al., 2004). as single chain preproenzymes of approximately 30–40 kDa Serine proteases exhibit diverse functions in digestion, co- (Fig. 1)(Obiezu and Diamandis, 2005). The signal (pre-) se- agulation, and cellular and humoral immunity (Rawlings and quence is 16–30 amino acids in length and is cleaved from Barrett, 1994). Based on their evolutionary relationships, ser- the N-terminus of the protein prior to secretion (Yousef and ine proteases can further be grouped into eleven clans (Raw- Diamandis, 2001). Enzyme activation may subsequently occur lings and Barrett, 1994). The trypsin/chymotrypsin-like (clan through limited proteolysis targeted to the peptide bond be- SA) enzymes are considered as the main clan in the subfamily tween basic and hydrophobic residues of the ‘‘pro’’- sequence of the serine proteases (Rawlings and Barrett, 1994). (Gomis-Ruth et al., 2002)(Table 1). Characteristic to serine pro- Kallikrein-related peptidases belong to a subgroup of teases, KLKs contain a catalytic serine residue at their active secreted serine proteases within the S1 family of clan SA site cleft. Along with the active serine, histidine and aspartic (Borgono et al., 2004). So far, fifteen members of the family acid residues of the catalytic triad, serve as a charge relay sys- (KLK1-15) have been identified, most of which have been tem (Obiezu and Diamandis, 2005; Gomis-Ruth et al., 2002). reported as potential prognostic and/or diagnostic tumour KLKs share a high level of amino acid identity in areas biomarkers. flanking the catalytic triad (Obiezu and Diamandis, 2005). The initial work in the kallikrein-related peptidase re- The overall sequence similarity, however, is estimated at search was devoted to the discovery and characterization of a lower level (40%–80%) with highest sequence similarity the three members of the family known as the ‘‘classic’’ kalli- between the ‘‘classic’’ KLKs (Obiezu and Diamandis, 2005). krein-related peptidases (KLK1, 2, and 3), during 1930s–1980s So far, the 3D structure of mature KLK1, KLK4, and both (Borgono et al., 2004). Subsequent work from our laboratory mature and pro-KLK6 have been determined by X-ray crystal- and others has eventually led to the characterization of twelve lography (Debela et al., 2006a; Laxmikanthan et al., 2005; Ber- novel members in the past decade. nett et al., 2002; Gomis-Ruth et al., 2002). As a subgroup of the According to the official nomenclature system recommen- trypsin/chymotrypsin-like serine proteases, these KLKs are ded by the Kallikrein subcommittee of HGNC (HUGO Nomen- folded into two hydrophobically interacting domains of six- clature Committee) in 2006, kallikrein-related peptidases are stranded b-barrels and an a-helix. The catalytic triad is located denoted as KLKs (Lundwall et al., 2006a). To distinguish be- at the interface between the two domains, as a shallow tween proteins and genes, proteins are written in standard depression on the frontal surface (Debela et al., 2006a; font, e.g. KLK2, while genes are in italics, e.g. KLK2. Gomis-Ruth et al., 2002; Bernett et al., 2002). KLK1 contains an additional ‘‘kallikrein loop’’, unique to the ‘‘classic’’ KLKs (Laxmikanthan et al., 2005). The loop consists of 11 amino 2. Gene organization and protein structure acids, inserted at position 95 (Laxmikanthan et al., 2005). Given its close proximity to the active site, the kallikrein KLKs are encoded by a cluster of strikingly similar genes loop is believed to affect the substrate accessibility of the en- with varying length, ranging from 4.4 to 10.5 kbp (Obiezu
Load more

Recommended publications
  • Functional Characterization of BC039389-GATM and KLK4
    Pflueger et al. BMC Genomics (2015) 16:247 DOI 10.1186/s12864-015-1446-z RESEARCH ARTICLE Open Access Functional characterization of BC039389-GATM and KLK4-KRSP1 chimeric read-through transcripts which are up-regulated in renal cell cancer Dorothee Pflueger1,2, Christiane Mittmann1, Silvia Dehler3, Mark A Rubin4,5, Holger Moch1,2 and Peter Schraml1* Abstract Background: Chimeric read-through RNAs are transcripts originating from two directly adjacent genes (<10 kb) on the same DNA strand. Although they are found in next-generation whole transcriptome sequencing (RNA-Seq) data on a regular basis, investigating them further has usually been refrained from. Therefore, their expression patterns or functions in general, and in oncogenesis in particular, are poorly understood. Results: We used paired-end RNA-Seq and a specifically designed computational data analysis pipeline (FusionSeq) to nominate read-through events in a small discovery set of renal cell carcinomas (RCC) and confirmed them in a larger validation cohort. 324 read-through events were called overall; 22/27 (81%) selected nominees passed validation with conventional PCR and were sequenced at the junction region. We frequently identified various isoforms of a given read-through event. 2/22 read-throughs were up-regulated: BC039389-GATM was higher expressed in RCC compared to benign adjacent kidney; KLK4-KRSP1 was expressed in 46/169 (27%) RCCs, but rarely in normal tissue. KLK4-KRSP1 expression was associated with worse clinical outcome in the patient cohort. In cell lines, both read-throughs influenced molecular mechanisms (i.e. target gene expression or migration/invasion) in a way that counteracted the effect of the respective parent transcript GATM or KLK4.
    [Show full text]
  • Table of Contents
    Table of Contents Preface V List of contributing authors VII Table of Contents XI Introduction to Volume 1: Kallikrein-related Peptidases. Characterization, Regulation, and Interactions Within the Protease Web 1 Bibliography 3 1 Genomic Structure of the KLK Locus 5 1.1 Introduction 5 1.2 Kallikreins in rodents 6 1.2.1 The mouse kallikrein gene family 7 1.2.2 The rat kallikrein gene family 8 1.3 Characterization and sequence analysis of the human KLK gene locus 9 1.3.1 Locus overview 9 1.3.2 Repeat elements and pleomorphism 11 1.4 Structural features of the human KLK genes and proteins 12 1.4.1 Common structural features 12 1.5 Sequence variations of human KLK genes 13 1.6 Regulation of KLK activity 14 1.6.1 At the mRNA level 14 1.6.2 Locus control of KLK expression 15 1.6.3 Epigenetic regulation of KLK gene expression 17 1.7 Isoforms and splice variants of human KLKs 18 1.8 Evolution of KLKs 21 Bibliography 22 2 Single Nucleotide Polymorphisms in the Human KLK Locus and Their Implication in Various Diseases 31 2.1 Introduction 31 2.2 KLK SNPs – data-mining from SNPdb and 1000 Genomes 32 2.3 Functional annotations using web-based prediction tools 34 2.4 Experimentally validated functional KLK SNPs 35 2.5 KLK SNP haplotypes and tagging 36 2.6 Malignant and non-malignant diseases and association with KLK SNPs 38 2.6.1 Association studies on high-risk variants in KLK genes 39 XII Table of Contents 2.6.2 Association studies on low-risk variants in KLK genes 39 2.7 Conclusions 71 Bibliography 71 3 Evolution of Kallikrein-related Peptidases 79
    [Show full text]
  • Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease
    Supplementary Online Content Ganz P, Heidecker B, Hveem K, et al. Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease. JAMA. doi: 10.1001/jama.2016.5951 eTable 1. List of 1130 Proteins Measured by Somalogic’s Modified Aptamer-Based Proteomic Assay eTable 2. Coefficients for Weibull Recalibration Model Applied to 9-Protein Model eFigure 1. Median Protein Levels in Derivation and Validation Cohort eTable 3. Coefficients for the Recalibration Model Applied to Refit Framingham eFigure 2. Calibration Plots for the Refit Framingham Model eTable 4. List of 200 Proteins Associated With the Risk of MI, Stroke, Heart Failure, and Death eFigure 3. Hazard Ratios of Lasso Selected Proteins for Primary End Point of MI, Stroke, Heart Failure, and Death eFigure 4. 9-Protein Prognostic Model Hazard Ratios Adjusted for Framingham Variables eFigure 5. 9-Protein Risk Scores by Event Type This supplementary material has been provided by the authors to give readers additional information about their work. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Supplemental Material Table of Contents 1 Study Design and Data Processing ......................................................................................................... 3 2 Table of 1130 Proteins Measured .......................................................................................................... 4 3 Variable Selection and Statistical Modeling ........................................................................................
    [Show full text]
  • Original Article KLK4 Is Synchronically Expressed to CTSC in Ameloblasts During Amelogenesis Molars
    Int J Clin Exp Pathol 2017;10(5):5751-5757 www.ijcep.com /ISSN:1936-2625/IJCEP0047909 Original Article KLK4 is synchronically expressed to CTSC in ameloblasts during amelogenesis molars Lijie Wang1,2*, Xiaohua Xie1*, Yunduan Sun3, Jingyu Wang1, Yan Wang1, Xiumei Wang1 1Department of Stomatology, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China; 2Department of Stomatology, General Hospital of Daqing Oil Field, Daqing, Heilongjiang Prov- ince, China; 3The 1st Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China. *Equal contributors. Received January 2, 2017; Accepted January 27, 2017; Epub May 1, 2017; Published May 15, 2017 Abstract: The aim of this study was to provide the evidence that the CTSC product, DPPI is the activator of KLK4 dur- ing amelogenesis by examining the expression pattern of KLK4 and CTSC in developing teeth. The 1st mandibular molars from E16.5 embryos and postnatal mice, and incisor from P5 mandibles were selected for the immunohisto- chemistry with antibodies against KLK4 and DPPI. The expression of KLK4 and CTSC were initiated from postnatal day 1 (P1) expressed in molar ameloblasts. From P5 on, KLK4 was distributed not only in ameloblasts, but also in the degenerating satellite reticulum of molar enamel organ. However, DPPI distribution is always restricted to the molar ameloblasts. In the P5 incisor, the distribution of KLK4 and DPPI were spatiotemporally consistent in the ameloblasts. The coincidence of KLK4 and DPPI distribution in ameloblasts strongly suggested that DPPI activated KLK4. The distribution of KLK4 in satellite reticulum suggested that KLK4 most likely plays a proteolytic role in degeneration of enamel organ.
    [Show full text]
  • Download, Or Email Articles for Individual Use
    Florida State University Libraries Faculty Publications The Department of Biomedical Sciences 2010 Functional Intersection of the Kallikrein- Related Peptidases (KLKs) and Thrombostasis Axis Michael Blaber, Hyesook Yoon, Maria Juliano, Isobel Scarisbrick, and Sachiko Blaber Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected] Article in press - uncorrected proof Biol. Chem., Vol. 391, pp. 311–320, April 2010 • Copyright ᮊ by Walter de Gruyter • Berlin • New York. DOI 10.1515/BC.2010.024 Review Functional intersection of the kallikrein-related peptidases (KLKs) and thrombostasis axis Michael Blaber1,*, Hyesook Yoon1, Maria A. locus (Gan et al., 2000; Harvey et al., 2000; Yousef et al., Juliano2, Isobel A. Scarisbrick3 and Sachiko I. 2000), as well as the adoption of a commonly accepted Blaber1 nomenclature (Lundwall et al., 2006), resolved these two fundamental issues. The vast body of work has associated 1 Department of Biomedical Sciences, Florida State several cancer pathologies with differential regulation or University, Tallahassee, FL 32306-4300, USA expression of individual members of the KLK family, and 2 Department of Biophysics, Escola Paulista de Medicina, has served to elevate the importance of the KLKs in serious Universidade Federal de Sao Paulo, Rua Tres de Maio 100, human disease and their diagnosis (Diamandis et al., 2000; 04044-20 Sao Paulo, Brazil Diamandis and Yousef, 2001; Yousef and Diamandis, 2001, 3 Program for Molecular Neuroscience and Departments of 2003;
    [Show full text]
  • Figure S1. Reverse Transcription‑Quantitative PCR Analysis of ETV5 Mrna Expression Levels in Parental and ETV5 Stable Transfectants
    Figure S1. Reverse transcription‑quantitative PCR analysis of ETV5 mRNA expression levels in parental and ETV5 stable transfectants. (A) Hec1a and Hec1a‑ETV5 EC cell lines; (B) Ishikawa and Ishikawa‑ETV5 EC cell lines. **P<0.005, unpaired Student's t‑test. EC, endometrial cancer; ETV5, ETS variant transcription factor 5. Figure S2. Survival analysis of sample clusters 1‑4. Kaplan Meier graphs for (A) recurrence‑free and (B) overall survival. Survival curves were constructed using the Kaplan‑Meier method, and differences between sample cluster curves were analyzed by log‑rank test. Figure S3. ROC analysis of hub genes. For each gene, ROC curve (left) and mRNA expression levels (right) in control (n=35) and tumor (n=545) samples from The Cancer Genome Atlas Uterine Corpus Endometrioid Cancer cohort are shown. mRNA levels are expressed as Log2(x+1), where ‘x’ is the RSEM normalized expression value. ROC, receiver operating characteristic. Table SI. Clinicopathological characteristics of the GSE17025 dataset. Characteristic n % Atrophic endometrium 12 (postmenopausal) (Control group) Tumor stage I 91 100 Histology Endometrioid adenocarcinoma 79 86.81 Papillary serous 12 13.19 Histological grade Grade 1 30 32.97 Grade 2 36 39.56 Grade 3 25 27.47 Myometrial invasiona Superficial (<50%) 67 74.44 Deep (>50%) 23 25.56 aMyometrial invasion information was available for 90 of 91 tumor samples. Table SII. Clinicopathological characteristics of The Cancer Genome Atlas Uterine Corpus Endometrioid Cancer dataset. Characteristic n % Solid tissue normal 16 Tumor samples Stagea I 226 68.278 II 19 5.740 III 70 21.148 IV 16 4.834 Histology Endometrioid 271 81.381 Mixed 10 3.003 Serous 52 15.616 Histological grade Grade 1 78 23.423 Grade 2 91 27.327 Grade 3 164 49.249 Molecular subtypeb POLE 17 7.328 MSI 65 28.017 CN Low 90 38.793 CN High 60 25.862 CN, copy number; MSI, microsatellite instability; POLE, DNA polymerase ε.
    [Show full text]
  • Functional and Structural Insights Into Astacin Metallopeptidases
    Biol. Chem., Vol. 393, pp. 1027–1041, October 2012 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/hsz-2012-0149 Review Functional and structural insights into astacin metallopeptidases F. Xavier Gomis-R ü th 1, *, Sergio Trillo-Muyo 1 Keywords: bone morphogenetic protein; catalytic domain; and Walter St ö cker 2, * meprin; metzincin; tolloid; zinc metallopeptidase. 1 Proteolysis Lab , Molecular Biology Institute of Barcelona, CSIC, Barcelona Science Park, Helix Building, c/Baldiri Reixac, 15-21, E-08028 Barcelona , Spain Introduction: a short historical background 2 Institute of Zoology , Cell and Matrix Biology, Johannes Gutenberg University, Johannes-von-M ü ller-Weg 6, The fi rst report on the digestive protease astacin from the D-55128 Mainz , Germany European freshwater crayfi sh, Astacus astacus L. – then termed ‘ crayfi sh small-molecule protease ’ or ‘ Astacus pro- * Corresponding authors tease ’ – dates back to the late 1960s (Sonneborn et al. , 1969 ). e-mail: [email protected]; [email protected] Protein sequencing by Zwilling and co-workers in the 1980s did not reveal homology to any other protein (Titani et al. , Abstract 1987 ). Shortly after, the enzyme was identifi ed as a zinc met- allopeptidase (St ö cker et al., 1988 ), and other family mem- The astacins are a family of multi-domain metallopepti- bers emerged. The fi rst of these was bone morphogenetic β dases with manifold functions in metabolism. They are protein 1 (BMP1), a protease co-purifi ed with TGF -like either secreted or membrane-anchored and are regulated growth factors termed bone morphogenetic proteins due by being synthesized as inactive zymogens and also by co- to their capacity to induce ectopic bone formation in mice localizing protein inhibitors.
    [Show full text]
  • Clinical Significance of Kallikrein-Related Peptidase-4 in Oral Cancer
    ANTICANCER RESEARCH 35: 1861-1866 (2015) Clinical Significance of Kallikrein-related Peptidase-4 in Oral Cancer PETROS PAPAGERAKIS1,2, GIUSEPPE PANNONE3, LI ZHENG1,4, MARIA ATHANASSIOU-PAPAEFTHYMIOU1,4, YASHUO YAMAKOSHI5, HOWARD STAN MCGUFF6, OMAR SHKEIR4, KONSTANTINOS GHIRTIS1,4 and SILVANA PAPAGERAKIS4 Departments of 1Pediatric Dentistry and Orthodontics and 5Biomaterials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, U.S.A.; Departments of 2Computational Medicine and Bioinformatics and 4Otolaryngology-Head & Neck Surgery, Medical School, University of Michigan, Ann Arbor, MI, U.S.A.; 3Department of Clinical and Experimental Medicine, Section of Anatomic Pathology, University of Foggia, Foggia, Italy; 6Department of Pathology, School of Medicine, University of Texas Health Science Center, San Antonio, TX, U.S.A. Abstract. Kallikrein-related-peptidase-4 (KLK4), a serine zymograms. Inhibition of KLK4 expression results in protease originally discovered in developing tooth with broad diminished invasive potential in OSCC cell lines. Consistently, target sequence specificity, serves vital functions in dental KLK4 expression is stronger in primary tumors that later enamel formation. KLK4 is involved in degradation of extra - either recurred or developed metastases, suggesting that its cellular matrix proteins and it is thought that this proteolytic preferential expression in OSCC might contribute to activity could also promote tumor invasion and metastasis. individual tumor biology. Therefore, this study provides Recent studies have associated KLK4 expression with tumor supportive evidence in favor of a prognostic value for KLK4 progression and clinical outcome, particularly in prostate and in OSCC and suggests that KLK4 could serve as a potential ovarian cancer. Very little is known in regard KLK4 therapeutic target in patients with oral cancer.
    [Show full text]
  • Activation Profiles and Regulatory Cascades of the Human Kallikrein-Related Peptidases Hyesook Yoon
    Florida State University Libraries Electronic Theses, Treatises and Dissertations The Graduate School 2008 Activation Profiles and Regulatory Cascades of the Human Kallikrein-Related Peptidases Hyesook Yoon Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected] FLORIDA STATE UNIVERSITY COLLEGE OF ARTS AND SCIENCES ACTIVATION PROFILES AND REGULATORY CASCADES OF THE HUMAN KALLIKREIN-RELATED PEPTIDASES By HYESOOK YOON A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy Degree Awarded: Fall Semester, 2008 The members of the Committee approve the dissertation of Hyesook Yoon defended on July 10th, 2008. ________________________ Michael Blaber Professor Directing Dissertation ________________________ Hengli Tang Outside Committee Member ________________________ Brian Miller Committee Member ________________________ Oliver Steinbock Committee Member Approved: ____________________________________________________________ Joseph B. Schlenoff, Chair, Department of Chemistry and Biochemistry The Office of Graduate Studies has verified and approved the above named committee members. ii ACKNOWLEDGMENTS I would like to dedicate this dissertation to my parents for all your support, and my sister and brother. I would also like to give great thank my advisor, Dr. Blaber for his patience, guidance. Without him, I could never make this achievement. I would like to thank to all the members in Blaber lab. They are just like family to me and I deeply appreciate their kindness, consideration and supports. I specially like to thank to Mrs. Sachiko Blaber for her endless guidance and encouragement. I would like to thank Dr Jihun Lee, Margaret Seavy, Rani and Doris Terry for helpful discussions and supports.
    [Show full text]
  • A Multiparametric Serum Kallikrein Panel for Diagnosis of Non ^ Small
    Imaging, Diagnosis, Prognosis A Multiparametric Serum Kallikrein Panel for Diagnosis of Non ^ Small Cell Lung Carcinoma Chris Planque,1, 2 Lin Li,3 Yingye Zheng,3 Antoninus Soosaipillai,1, 2 Karen Reckamp,4 David Chia,5 Eleftherios P. Diamandis,1, 2 and Lee Goodglick5 Abstract Purpose: Human tissue kallikreins are a family of15 secreted serine proteases.We have previous- ly shown that the expression of several tissue kallikreins is significantly altered at the transcription- al level in lung cancer. Here, we examined the clinical value of 11members of the tissue kallikrein family as potential biomarkers for lung cancer diagnosis. Experimental Design: Serum specimens from 51 patients with non ^ small cell lung cancer (NSCLC) and from 50 healthy volunteers were collected. Samples were analyzed for11kallikreins (KLK1, KLK4-8, and KLK10-14) by specific ELISA. Data were statistically compared and receiver operating characteristic curves were constructed for each kallikrein and for various combinations. Results: Compared with sera from normal subjects, sera of patients with NSCLC had lower levels of KLK5, KLK7, KLK8, KLK10, and KLK12, and higher levels of KLK11, KLK13, and KLK14. Expres- sion of KLK11and KLK12 was positively correlated with stage.With the exception of KLK5, expres- sion of kallikreins was independent of smoking status and gender. KLK11, KLK12, KLK13, and KLK14 were associated with higher risk of NSCLC as determined by univariate analysis and con- firmed by multivariate analysis.The receiver operating characteristic curve of KLK4, KLK8, KLK10, KLK11,KLK12, KLK13, and KLK14 combined exhibited an area under the curve of 0.90 (95% con- fidence interval, 0.87-0.97).
    [Show full text]
  • Aberrant KLK4 Gene Promoter Hypomethylation in Pediatric Hepatoblastomas
    1360 ONCOLOGY LETTERS 13: 1360-1364, 2017 Aberrant KLK4 gene promoter hypomethylation in pediatric hepatoblastomas BAIHUI LIU*, XIMAO CUI*, SHAN ZHENG, KUIRAN DONG and RUI DONG Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defects and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai 201102, P.R. China Received June 16, 2015; Accepted October 24, 2016 DOI: 10.3892/ol.2017.5558 Abstract. DNA methylation has a crucial role in cancer Introduction biology and has been recognized as an activator of onco- genes and inactivator of tumor suppressor genes, both of Hepatoblastoma (HB) is the most common type of malignant which are mechanisms for tumorigenesis. Kallikrein-related liver tumor in infants and children. Although it accounts for peptidase 4 (KLK4), has been suggested to be an oncogene just 0.5-1.5 cases per million children per year, the mortality in various types of cancer. The aim of the present study was rate is 35-50% in high-risk patients (1). Previous studies have to assess the DNA methylation patterns of the KLK4 gene suggested an association with familial adenomatous polyposis in cancerous samples harvested from patients with hepato- (FAP) (2), both low and high birth weights (3), and constitu- blastoma (HB). KLK4 mRNA expression levels were detected tional trisomy 18 (4); however its etiology remains unknown. using reverse transcription-quantitative polymerase chain Currently, alphafetoprotein levels, histological analysis, reaction and assessed its DNA methylation patterns using tumor resectability and tumor metastasis are the only prognosis high-throughput mass spectrometry on a matrix-assisted laser factors for HB.
    [Show full text]
  • Download CGT Exome V2.0
    CGT Exome version 2.
    [Show full text]