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  • 1.
    Bergström, Sven
    et al.
    Umeå University, Faculty of Medicine, Microbiology.
    Olsén, Björn
    Umeå University, Faculty of Medicine, Microbiology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Burman, Nils
    Umeå University, Faculty of Medicine, Microbiology.
    Gothefors, Leif
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Jaenson, Thomas G.T.
    University of Uppsala.
    Jonsson, Maria
    Umeå University, Faculty of Medicine, Microbiology.
    Mejlon, Hans A
    University of Uppsala.
    Molecular characterization of Borrelia burgdorferi isolated from Ixodes ricinus in northern Sweden1992In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 24, no 2, p. 181-188Article in journal (Refereed)
    Abstract [en]

    Ixodes ricinus ticks, harbouring Borrelia burgdorferi, were found in an area in northern Sweden, not thought to be endemic for Lyme borreliosis. This investigation took place at Norrbyskär, an island situated in the Bothnian Gulf, 63 degrees 33'N/19 degrees 52'E. One of 42 nymphal and 8/43 adult I. ricinus ticks collected carried spirochetes as seen by phase contrast microscopy. Pure bacterial cultures were obtained from 2 of the ticks. Western blot analysis using species-specific monoclonal antibodies showed that the isolated spirochetes were B. burgdorferi. The identity of the isolated spirochetes was confirmed by DNA amplification using B. burgdorferi OspA and flagellin gene specific oligonucleotides as well as partial DNA sequencing of the respective OspA and flagellin genes. The 2 isolated spirochaete populations were different as shown by their protein profiles in sodium dodecyl sulphate polyacrylamide gels. Moreover, the demonstration of Lyme borreliosis in a patient from the island of Norrbyskär indicates the need for clinical consideration of this disease in northern Sweden.

  • 2.
    Bovinder Ylitalo, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thellenberg-Karlsson, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lundholm, Marie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Excellent cabazitaxel response in prostate cancer xenografts expressing androgen receptor variant 7 and reversion of resistance development by anti-androgensManuscript (preprint) (Other academic)
  • 3.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Kallikrein-related peptidases and inhibitors of the skin2012In: Kallikrein-related peptidases: characterization, regulation, and interactions within the protease web / [ed] Viktor Magdolen, Christian P. Sommerhoff, Hans Fritz and Manfred Schmitt, Berlin: Walter de Gruyter, 2012, p. 329-347Chapter in book (Refereed)
  • 4.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Kan KLK7 vara en användbar biomarkör för progression av melanom?2018In: BestPractice Dermatologi, Vol. 9, no 25Article, review/survey (Refereed)
  • 5.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Missing factors in human skin equivalent models?2017In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 176, no 1, p. 11-12Article in journal (Refereed)
  • 6.
    Brattsand, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Egelrud, Torbjörn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Purification and characterization of interleukin 1 beta from human plantar stratum corneum. Evidence of interleukin 1 beta processing in vivo not involving interleukin 1 beta convertase1998In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 10, no 7, p. 506-513Article in journal (Refereed)
    Abstract [en]

    The major interleukin 1 beta (IL-1 beta) species from human plantar stratum corneum was purified and found to have an N-terminal amino acid sequence homologous to a stretch of the human IL-1 beta precursor, starting with His115. Whereas SDS-polyacrylamide gel electrophoresis followed by immunoblotting revealed only one component in plantar stratum corneum with IL-1 beta-like immunoreactivity, and with an apparent molecular mass around 18 kDa, isoelectric focusing under non-denaturing conditions showed one major component with isoelectric point around 6.1 and two minor components isoelectric at pH 6.3 and 6.9, respectively. Digestion of recombinant human IL-1 beta precursor with chymotrypsin, producing a C-terminal fragment with N-terminal Yal114, yielded a component with IL-1 beta-like immunoreactivity isoelectric at pH 6.3. Recombinant bacterial variants of human IL-1 beta with N-terminal amino acids corresponding to Val114, His115 and Ala117 were isoelectric at pH 6.3, 6.1 and 6.9, respectively. Cloning and subsequent nucleotide sequencing of IL-1 beta precursor cDNA from a human keratinocyte line showed total identify with the sequence previously published for the human monocyte IL-1 beta precursor. The authors conclude that the IL-1 beta species present in plantar stratum corneum have isoelectric points determined by their respective amino acid sequences, and that there is a mechanism for IL-1 beta activation in human epidermis not involving interleukin 1 beta convertase.

  • 7.
    Brattsand, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Egelrud, Torbjörn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Purification, molecular cloning, and expression of a human stratum corneum trypsin-like serine protease with possible function in desquamation1999In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 274, no 42, p. 30033-40Article in journal (Refereed)
    Abstract [en]

    A new human 33-kDa serine protease was purified from human epidermis, and its cDNA was cloned from a keratinocyte library, from mRNA from a human keratinocyte line (HaCat) and from mRNA from human skin. Polyclonal antibodies specific for the new protein detected three groups of proteins in partially purified extracts of cornified eptihelium of human plantar skin. The three components are proposed to correspond to proenzyme, active enzyme, and proteolytically modified active enzyme. After N-deglycosylation, there was a decrease in apparent molecular mass of all detected components. Expression of the cloned cDNA in a eukaryotic virus-derived system yielded a recombinant protein that could be converted to an active protease by treatment with trypsin. Polymerase chain reaction analyses of cDNA from a number of human tissues showed high expression of the new enzyme in the skin and low expression in brain, placenta, and kidney. Homology searches yielded the highest score for porcine enamel matrix protease (55% amino acid sequence homology). High scores were also obtained for human and mouse neuropsin and for human stratum corneum chymotryptic enzyme. The function of this new protease, tentatively named stratum corneum tryptic enzyme, may be related to stratum corneum turnover and desquamation in the epidermis.

  • 8.
    Brattsand, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Stefansson, Kristina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Hubiche, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Nilsson, Stefan K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Egelrud, Torbjörn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    SPINK9: a selective, skin-specific Kazal-type serine protease inhibitor.2009In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 129, no 7, p. 1656-1665Article in journal (Refereed)
    Abstract [en]

    A previously unreported Kazal-type serine protease inhibitor, serine protease inhibitor Kazal type 9 (SPINK9), was identified in human skin. SPINK9 expression was strong in palmar epidermis, but not detectable or very low in non palmoplantar skin. Analysis of a human cDNA panel showed intermediate expression in thymus, pancreas, liver, and brain, and low or undetectable expression in other tissues. Using kallikrein-related peptidases (KLKs) 5, 7, 8, and 14, thrombin, trypsin, and chymotrypsin, inhibition with recombinant SPINK9 was seen only for KLK5 using low molecular weight substrates, with an apparent K(i) of 65 nM. Also KLK5 degradation of fibrinogen was totally inhibited by SPINK9. Slight inhibition of KLK8 using fibrinogen substrate could be observed using high concentrations of SPINK9. Analyses by surface plasmon resonance showed heterogeneous binding to SPINK9 of KLK5 and KLK8, but no binding of KLK7 or KLK14. KLK5 has been suggested to play a central role in skin desquamation as an initiating activating enzyme in proteolytic cascades formed by KLKs. An apparently KLK5-specific inhibitor, such as SPINK9, may play a significant regulatory role in such cascades. We suggest a possible role for SPINK9 in the site-specific epidermal differentiation of palms and soles.

  • 9.
    Brattsand, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Stefansson, Kristina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Lundh, Christine
    Haasum, Ylva
    Egelrud, Torbjörn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    A proteolytic cascade of kallikreins in the stratum corneum2005In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 124, no 1, p. 198-203Article in journal (Refereed)
  • 10.
    Brännström, Kristoffer
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sellin, Mikael E
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Holmfeldt, Per
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Gullberg, Martin
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    The Schistosoma mansoni protein Sm16/SmSLP/SmSPO-1 assembles into a nine-subunit oligomer with potential To inhibit Toll-like receptor signaling.2009In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 77, no 3, p. 1144-1154Article in journal (Refereed)
    Abstract [en]

    The Sm16/SmSLP/SmSPO-1 (Sm16) protein is secreted by the parasite Schistosoma mansoni during skin penetration and has been ascribed immunosuppressive activities. Here we describe the strategy behind the design of a modified Sm16 protein with a decreased aggregation propensity, thus facilitating the expression and purification of an Sm16 protein that is soluble in physiological buffers. The Stokes radii and sedimentation coefficients of recombinant and native proteins indicate that Sm16 is an approximately nine-subunit oligomer. Analysis of truncated Sm16 derivatives showed that both oligomerization and binding to the plasma membrane of human cells depend on multiple C-terminal regions. For analysis of immunomodulatory activities, Sm16 was expressed in Pichia pastoris to facilitate the preparation of a pyrogen/endotoxin-free purified protein. Recombinant Sm16 was found to have no effect on T-lymphocyte activation, cell proliferation, or the basal level of cytokine production by whole human blood or monocytic cells. However, Sm16 exerts potent inhibition of the cytokine response to the Toll-like receptor (TLR) ligands lipopolysaccharide (LPS) and poly(I:C) while being less efficient at inhibiting the response to the TLR ligand peptidoglycan or a synthetic lipopeptide. Since Sm16 specifically inhibits the degradation of the IRAK1 signaling protein in LPS-stimulated monocytes, our findings indicate that inhibition is exerted proximal to the TLR complex.

  • 11.
    Brännström, Kristoffer
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Öhman, Anders
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    von Pawel-Rammingen, Ulrich
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Olofsson, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Characterization of SPINK9, a KLK5-specific inhibitor expressed in palmo-plantar epidermis2012In: Biological chemistry (Print), ISSN 1431-6730, E-ISSN 1437-4315, Vol. 393, no 5, p. 369-377Article in journal (Refereed)
    Abstract [en]

    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.

  • 12.
    Bäckman, Assar
    et al.
    Astra Hässle AB, Umeå, Sweden.
    Strandén, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Brattsand, Maria
    Hansson, Lennart
    Astra Hässle AB, Umeå, Sweden.
    Egelrud, Torbjörn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Molecular cloning and tissue expression of the murine analog to human stratum corneum chymotryptic enzyme1999In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 113, no 2, p. 152-5Article in journal (Refereed)
    Abstract [en]

    Human stratum corneum chymotryptic enzyme (SCCE) may play a central part in epidermal homeostasis. Its proposed function is to catalyze the degradation of intercellular structures, including desmosomes, in the stratum corneum as part of the desquamation process. In order to facilitate physiologic and pathophysiologic studies on SCCE we have looked for the corresponding murine enzyme. A cDNA obtained by reverse transcription-polymerase chain reaction with total RNA prepared from mouse tails as starting material was cloned, and the expression of the corresponding mRNA studied. The murine cDNA showed 77% homology to human SCCE cDNA. It had an open-reading frame encoding a protein comprising 249 amino acids with 82% amino acid sequence homology to human SCCE including the conserved sequences of the catalytic traid of mammalian serine proteases. The murine protein was deduced to have a 21 amino acid signal peptide and a four amino acid propeptide ending with a tryptic cleavage site, followed by a sequence motif identical to the N-terminal amino acid sequence of native active human SCCE. As in human SCCE the P2 position of the propeptide was occupied by an acidic amino acid residue, and the position corresponding to the suggested bottom of the primary substrate specificity pouch occupied by an asparagine residue. Analyses of mouse tissues by reverse transcriptase-polymerase chain reaction showed high expression in the skin, low expression in lung, kidney, brain, heart, and spleen, and no expression in liver or skeletal muscle. In situ hybridization of mouse skin showed expression in high suprabasal keratinocytes and in the luminal parts of hair follicles. Our results strongly suggest that we have cloned the murine analog of human SCCE cDNA.

  • 13. Caubet, Cécile
    et al.
    Jonca, Nathalie
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Dermatology and Venerology.
    Guerrin, Marina
    Bernard, Dominique
    Schmidt, Rainer
    Egelrud, Torbjörn
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Dermatology and Venerology.
    Simon, Michel
    Serre, Guy
    Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7.2004In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 122, no 5, p. 1235-1244Article in journal (Refereed)
  • 14. Chen, Xingchen
    et al.
    Riley, Blake T.
    de Veer, Simon J.
    Hoke, David E.
    Van Haeften, Jessica
    Leahy, Darren
    Swedberg, Joakim E.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hartfield, Perry J.
    Buckle, Ashley M.
    Harris, Jonathan M.
    Potent, multi-target serine protease inhibition achieved by a simplified beta-sheet motif2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 1, article id e0210842Article in journal (Refereed)
    Abstract [en]

    Engagement of an extended beta-sheet is a common substrate/inhibitor interaction at the active site of serine proteases and is an important feature of Laskowski mechanism inhibitors that present a substrate-like loop to a target protease. This loop is cleaved but subsequently relegated forming a stable inhibitor/protease complex. Laskowski inhibitors are ubiquitous in nature and are used extensively in serine protease inhibitor design. However, most studies concentrate on introducing new sidechain interactions rather than the direct contributions of the substrate-like beta-sheet to enzyme inhibition. Here we report the crystal structure of an simplified beta-sheet inhibitory motif within the Sunflower Trypsin Inhibitor (SFTI) in complex with trypsin. We show that the intramolecular hydrogen bond network of this SFTI variant (SFTI-TCTR) engages the inhibitor sidechains that would normally interact with a target protease, giving mainchain interactions a more prominent role in complex formation. Despite having reduced sidechain interactions, this SFTI variant is remarkably potent and inhibits a diverse range of serine proteases. Crystal structural analysis and molecular modelling of SFTI-TCTR complexes again indicates an interface dominated by beta-sheet interactions, highlighting the importance of this motif and the adaptability of SFTI as a scaffold for inhibitor design.

  • 15. de Veer, Simon J.
    et al.
    Furio, Laetitia
    Swedberg, Joakim E.
    Munro, Christopher A.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Clements, Judith A.
    Hovnanian, Alain
    Harris, Jonathan M.
    Selective Substrates and Inhibitors for Kallikrein-Related Peptidase 7 (KLK7) Shed Light on KLK Proteolytic Activity in the Stratum Corneum2017In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 137, no 2, p. 430-439Article in journal (Refereed)
    Abstract [en]

    Proteases have pivotal roles in the skin's outermost layer, the epidermis. In the stratum corneum, serine proteases from the kallikrein-related peptidase (KLK) family have been implicated in several key homeostatic processes, including desquamation. However, the precise contribution of specific KLKs to each process remains unclear. To address this, we used a chemical biology approach and designed selective substrates and inhibitors for KLK7, the most abundant KLK protease in the stratum corneum. The resulting KLK7 inhibitor is the most potent inhibitor of this protease reported to date (K-i = 140 pM), and displays at least 1,000-fold selectivity over several proteases that are related by function (KLK5 and KLK14) or specificity (chymotrypsin). We then used substrates and inhibitors for KLK5, KLK7, and KLK14 to explore the activity of each protease in the stratum corneum using casein zymography and an ex vivo desquamation assay. These experiments provide the most detailed assessment of each KLK's contribution to corneocyte shedding in the plantar stratum corneum, revealing that inhibition of KLK7 alone is sufficient to block shedding, whereas KLK5 is also a major contributor. Collectively, these findings unveil chemical tools for studying KLK activity and demonstrate their potential for characterizing KLK biological functions in epidermal homeostasis.

  • 16. de Veer, Simon J.
    et al.
    Swedberg, Joakim E.
    Akcan, Muharrem
    Rosengren, K. Johan
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Craik, David J.
    Harris, Jonathan M.
    Engineered protease inhibitors based on sunflower trypsin inhibitor-1 (SFTI-1) provide insights into the role of sequence and conformation in Laskowski mechanism inhibition2015In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 469, no 2, p. 243-253Article in journal (Refereed)
    Abstract [en]

    Laskowski inhibitors regulate serine proteases by an intriguing mode of action that involves deceiving the protease into synthesizing a peptide bond. Studies exploring naturally occurring Laskowski inhibitors have uncovered several structural features that convey the inhibitor's resistance to hydrolysis and exceptional binding affinity. However, in the context of Laskowski inhibitor engineering, the way that various modifications intended to fine-tune an inhibitor's potency and selectivity impact on its association and dissociation rates remains unclear. This information is important as Laskowski inhibitors are becoming increasingly used as design templates to develop new protease inhibitors for pharmaceutical applications. In this study, we used the cyclic peptide, sunflower trypsin inhibitor-1 (SFTI-1), as a model system to explore how the inhibitor's sequence and structure relate to its binding kinetics and function. Using enzyme assays, MD simulations and NMR spectroscopy to study SFTI variants with diverse sequence and backbone modifications, we show that the geometry of the binding loop mainly influences the inhibitor's potency by modulating the association rate, such that variants lacking a favourable conformation show dramatic losses in activity. Additionally, we show that the inhibitor's sequence (including both the binding loop and its scaffolding) influences its potency and selectivity by modulating both the association and the dissociation rates. These findings provide new insights into protease inhibitor function and design that we apply by engineering novel inhibitors for classical serine proteases, trypsin and chymotrypsin and two kallikrein-related peptidases (KLK5 and KLK14) that are implicated in various cancers and skin diseases.

  • 17. de Veer, Simon J.
    et al.
    Swedberg, Joakim E.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Clements, Judith A.
    Harris, Jonathan M.
    Exploring the active site binding specificity of kallikrein-related peptidase 5 (KLK5) guides the design of new peptide substrates and inhibitors2016In: Biological chemistry (Print), ISSN 1431-6730, E-ISSN 1437-4315, Vol. 397, no 12, p. 1237-1249Article in journal (Refereed)
    Abstract [en]

    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 (k(cat) and K-M) 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 (K-i = 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.

  • 18. Delaunay, Tiphaine
    et al.
    Deschamps, Lydia
    Haddada, Meriem
    Walker, Francine
    Soosaipillai, Antoninus
    Soualmia, Feryel
    El Amri, Chahrazade
    Diamandis, Eleftherios P
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Magdolen, Viktor
    Darmoul, Dalila
    Aberrant expression of kallikrein-related peptidase 7 is correlated with human melanoma aggressiveness by stimulating cell migration and invasion2017In: Molecular Oncology, ISSN 1574-7891, E-ISSN 1878-0261, Vol. 11, no 10, p. 1330-1347Article in journal (Refereed)
    Abstract [en]

    Members of the tissue kallikrein-related peptidase (KLK) family not only regulate several important physiological functions, but aberrant expression has also been associated with various malignancies. Clinically, KLKs have been suggested as promising biomarkers for diagnosis and prognosis in many types of cancer. As of yet, expression of KLKs and their role in skin cancers are, however, poorly addressed. Malignant melanoma is an aggressive disease associated with poor prognosis. Hence, diagnostic biomarkers to monitor melanoma progression are needed. Herein, we demonstrate that although mRNA of several KLKs are aberrantly expressed in melanoma cell lines, only the KLK7 protein is highly secreted in vitro. In line with these findings, ectopic expression of KLK7 in human melanomas and its absence in benign nevi were demonstrated by immunohistochemistry in vivo. Interestingly, overexpression of KLK7 induced a significant reduction in melanoma cell proliferation and colony formation. Moreover, KLK7 overexpression triggered an increase in cell motility and invasion associated with decreased expression of E-cadherin and an upregulation of MCAM/CD146. Our results demonstrate, for the first time, that aberrant KLK7 expression leads to a switch from proliferative to invasive phenotype, suggesting a potential role of KLK7 in melanoma progression. Thus, we hypothesize that KLK7 may represent a potential biomarker for melanoma progression.

  • 19. Deraison, Celine
    et al.
    Bonnart, Chrystelle
    Lopez, Frederic
    Besson, Celine
    Robinson, Ross
    Jayakumar, Arumugam
    Wagberg, Fredrik
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Hachem, Jean Pierre
    Leonardsson, Goran
    Hovnanian, Alain
    LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction.2007In: Molecular biology of the cell, ISSN 1059-1524, Vol. 18, no 9, p. 3607-3619Article in journal (Refereed)
  • 20.
    Djusberg, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jernberg, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lundberg, Pia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High Levels of the AR-V7 Splice Variant and Co-Amplification of the Golgi Protein Coding YIPF6 in AR Amplified Prostate Cancer Bone Metastases2017In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 77, no 6, p. 625-638Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The relation between androgen receptor (AR) gene amplification and other mechanisms behind castration-resistant prostate cancer (CRPC), such as expression of constitutively active AR variants and steroid-converting enzymes has been poorly examined. Specific aim was to examine AR amplification in PC bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying novel molecular targets for treatment. METHODS: Gene amplification was assessed by fluorescence in situ hybridization in cryo-sections of clinical PC bone metastases (n = 40) and by PCR-based copy number variation analysis. Whole genome mRNA expression was analyzed using H12 Illumina Beadchip arrays and specific transcript levels were quantified by qRT-PCR. Protein localization was analyzed using immunohistochemistry and confocal microscopy. The YIPF6 mRNA expression was transiently knocked down and stably overexpressed in the 22Rv1 cell line as representative for CRPC, and effects on cell proliferation, colony formation, migration, and invasion were determined in vitro. Extracellular vesicles (EVs) were isolated from cell cultures using size-exclusion chromatography and enumerated by nanoparticle tracking analysis. Protein content was identified by LC-MS/MS analysis. Blood coagulation was measured as activated partial thromboplastin time (APTT). Functional enrichment analysis was performed using the MetaCore software. RESULTS: AR amplification was detected in 16 (53%) of the bone metastases examined from CRPC patients (n = 30), and in none from the untreated patients (n = 10). Metastases with AR amplification showed high AR and AR-V7 mRNA levels, increased nuclear AR immunostaining, and co-amplification of genes such as YIPF6 in the AR proximity at Xq12. The YIPF6 protein was localized to the Golgi apparatus. YIPF6 overexpression in 22Rv1 cells resulted in reduced cell proliferation and colony formation, and in enhanced EV secretion. EVs from YIPF6 overproducing 22Rv1 cells were enriched for proteins involved in blood coagulation and, accordingly, decreased the APTT in a dose-dependent fashion. CONCLUSIONS: AR amplified CRPC bone metastases show high AR-V7 expression that probably gives resistance to AR-targeting drugs. Co-amplification of the Golgi protein coding YIPF6 gene with the AR may enhance the secretion of pro-coagulative EVs from cancer cells and thereby stimulate tumor progression and increase the coagulopathy risk in CRPC patients.

  • 21. Dong, Ying
    et al.
    Kaushal, Aneel
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Nicklin, Jim
    Clements, Judith A
    Differential splicing of KLK5 and KLK7 in epithelial ovarian cancer produces novel variants with potential as cancer biomarkers2003In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 9, no 5, p. 1710-20Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The wild-type or variant mRNAs of several kallikrein (KLK) genes, such as KLK4, are highly expressed in ovarian carcinomas and may have potential as tumor markers. Two of these KLK genes (KLK5 and KLK7) and their proteins (hK5 and hK7) were first identified in the skin epidermis, where hK5 may be the physiological activator of hK7. The purpose of this study was to reexamine the expression of KLK5/hK5 and KLK7/hK7 and their association and to determine whether cancer-related variant transcripts were expressed.

    EXPERIMENTAL DESIGN: The expression of KLK5/hK5 and KLK7/hK7 was analyzed in the same cohort (n = 37) of benign (n = 4) and malignant ovarian tissue (n = 23) samples and primary cultured cells (n = 21) and in 8 ovarian cancer cell lines using semiquantitative RT-PCR; Southern, Northern, and Western blot analyses; and immunohistochemistry techniques.

    RESULTS: We showed the concordant higher expression of both KLK5/hK5 and KLK7/hK7 in ovarian carcinomas, especially late-stage serous carcinomas, compared with normal ovaries and benign adenomas. We also found that one novel KLK5 transcript with a short 5'-untranslated region and a novel KLK7 transcript with a long 3'-untranslated region were highly expressed in the ovarian cancer cell lines OVCAR-3 and PEO1, respectively, but were expressed at very low levels in normal ovarian epithelial cells. Both Western blot and immunohistochemistry analyses showed that these two enzymes are secreted from ovarian carcinoma cells.

    CONCLUSIONS: Our study demonstrated that hK5 and hK7, or more specifically, the short KLK5 and long KLK7 transcripts, may be useful as tumor markers for epithelial-derived serous carcinomas. However, additional clinical studies assessing serum levels of these putative biomarkers are required to confirm their usefulness in the diagnosis and/or monitoring of these tumors.

  • 22.
    Egelrud, Torbjörn
    et al.
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Dermatology and Venerology.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Dermatology and Venerology.
    Kreutzmann, P
    Walden, M
    Vitzithum, K
    Marx, U C
    Forssmann, W G
    Mägert, H J
    hK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6.2005In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 153, no 6, p. 1200-1203Article in journal (Refereed)
  • 23.
    Ekholm, Elisabeth
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Sondell, Björn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Strandén, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Egelrud, Torbjörn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Expression of stratum corneum chymotryptic enzyme in human sebaceous follicles1998In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 78, no 5, p. 343-347Article in journal (Refereed)
    Abstract [en]

    Stratum corneum chymotryptic enzyme (SCCE) may be involved in desquamation, a process necessary for maintaining a normal anatomy at all sites where there is continuous turnover of cornified epithelia. Using immunohistochemistry and in situ hybridization, we have, in this work, analysed SCCE expression in the sebaceous follicle. We found expression of SCCE in luminal parts of the pilary canal, common sebaceous ducts and proximal sebaceous ducts. In addition, SCCE was seen in cells apparently situated within the distal parts of the glandular lobules. Co-expression of SCCE and keratin 10 was seen only in the pilary canal and the common sebaceous ducts. The results give further support for SCCE being involved in desquamation-like processes. The association with cornification seems to be more general for SCCE than for keratin 10. The possible role of SCCE in diseases involving disturbances in the turnover of cornified cells in the sebaceous follicle, such as acne vulgaris, is a question for future studies.

  • 24.
    Ekholm, I Elisabeth
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Egelrud, Torbjörn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Stratum corneum tryptic enzyme in normal epidermis: a missing link in the desquamation process?2000In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 114, no 1, p. 56-63Article in journal (Refereed)
    Abstract [en]

    Stratum corneum chymotryptic enzyme may be important in desquamation. It has also been suggested that other proteases, especially stratum corneum tryptic enzyme, may be involved. Stratum corneum tryptic enzyme has been purified and its cDNA has been cloned. Results from expression analyses indicate that stratum corneum tryptic enzyme is as skin specific as stratum corneum chymotryptic enzyme. In this work we have produced and characterized antibodies specific for stratum corneum tryptic enzyme. We have also by means of biochemical, immunochemical, and immunohistochemical methods performed studies on stratum corneum tryptic enzyme in normal human epidermis. Antibodies against bacterial recombinant stratum corneum tryptic enzyme were produced and purified by affinity chromatography. Two types of antibodies were obtained: one reacting only with pro-stratum corneum tryptic enzyme and one specific for the catalytically active part of stratum corneum tryptic enzyme. Immunohistochemistry with the antibodies reacting with pro-stratum corneum tryptic enzyme showed a staining pattern similar to stratum corneum chymotryptic enzyme-specific antibodies, i.e., the expression was confined to cornifying epithelia with a need of desquamation-like processes. Extracts of tape strips with superficial human stratum corneum were found to contain precursors as well as active forms of stratum corneum tryptic enzyme and stratum corneum chymotryptic enzyme. The enzymes had maximal activity at pH 8, but both had considerable activity also at pH 5.5. The results were compatible for a role of stratum corneum tryptic enzyme in desquamation. Stratum corneum tryptic enzyme may act in concert with stratum corneum chymotryptic enzyme and/or function as a stratum corneum chymotryptic enzyme-activating enzyme. The presence in normal superficial stratum corneum of precursors as well as of active forms of stratum corneum chymotryptic enzyme and stratum corneum tryptic enzyme, and the activity of both enzymes over a broad range of pH-values, suggest some possible ways by which the desquamation may be regulated.

  • 25. Hachem, Jean-Pierre
    et al.
    Wagberg, Fredrik
    Schmuth, Matthias
    Crumrine, Debra
    Lissens, Willy
    Jayakumar, Arumugam
    Houben, Evi
    Mauro, Theodora M
    Leonardsson, Göran
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Egelrud, Torbjorn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Roseeuw, Diane
    Clayman, Gary L
    Feingold, Kenneth R
    Williams, Mary L
    Elias, Peter M
    Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome2006In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 126, no 7, p. 1609-21Article in journal (Refereed)
  • 26. Haddada, Meriem
    et al.
    Draoui, Hend
    Deschamps, Lydia
    Walker, Francine
    Delaunay, Tiphaine
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Magdolen, Viktor
    Darmoul, Dalila
    Kallikrein-related peptidase 7 overexpression in melanoma cells modulates cell adhesion leading to a malignant phenotype2018In: Biological chemistry (Print), ISSN 1431-6730, E-ISSN 1437-4315, Vol. 399, no 9, p. 1099-1105Article in journal (Refereed)
    Abstract [en]

    We recently reported that human melanoma cells, but not benign melanocytes, aberrantly express kallikrein-related peptidase 7 (KLK7). Here, we show a KLK7 overexpression-mediated decrease of cell adhesion to extracellular matrix binding proteins, associated with downregulation of alpha 5/beta 1/alpha v/beta 3 integrin expression. We also report an up-regulation of MCAM/CD146 and an increase in spheroid formation of these cells. Our results demonstrate that aberrant KLK7 expression leads to a switch to a more malignant phenotype suggesting a potential role of KLK7 in melanoma invasion. Thus, KLK7 may represent a biomarker for melanoma progression and may be a potential therapeutic target for melanoma.

  • 27.
    Jernberg, Emma
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lundberg, Pia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Molecular features of prostate cancer bone metastases harboring androgen receptor gene amplificationManuscript (preprint) (Other academic)
    Abstract [en]

    The relation between AR amplification and other mechanisms behind castration-resistance in prostate cancer, such as increased expression of AR splice variants and steroid-converting enzymes in CRPC metastases, has been poorly examined. Specific aims of this study were therefore to examine AR amplification in hormone-naïve and castration-resistant prostate cancer (CRPC) bone metastases and to explore molecular and functional consequences of this, with the long-term goal of identifying molecular targets for treatment of CRPC bone metastases. AR amplification was assessed by fluorescence in situ hybridization and verified in 16 (53 %) of the CRPC bone metastases (n=30), and in none of the untreated bone metastases (n=10). AR amplification was associated with increased expression of AR and its constitutively active AR-V7 splice variant as well as with co-amplification of genes in the AR proximity at Xq12, such as of YIPF6. Furthermore, gene expression pattern pointed at decreased osteoclast activity, and consequently decreased bone resorption and increased bone mineral density in AR amplified metastases. In conclusion, our results indicated a sclerotic phenotype in CRPC bone metastases with AR amplification that may be of both biological and clinical relevance. This is a novel hypothesis that requires to be thoroughly examined.

  • 28.
    Jonsson, Maria
    Umeå University, Faculty of Medicine, Microbiology.
    Contribution of the outer surface proteins of Borrelia burgdorferi s.l. to the pathogenesis of Lyme disease1994Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Borrelia burgdorferi s. l. is a spirochete which causes the multisystemic disorder Lyme disease. As the borreliae lack toxin production, the pathogenicity is thought to involve, at least in part, molecules from the outer surface. Most Lyme disease Borrelia strains express two major outer surface lipoproteins, OspA (31 kD) and OspB (34 kD), on their surface. However, some strains lack the expression of OspA and OspB, but express a smaller 21 to 25 kD OspC protein instead. This thesis focuses on the importance of these proteins in the pathogenesis of Lyme disease.

    Biochemical and immunochemical studies of the OspA and OspB proteins from strains of various geographic origins show considerable differences in the apparent molecular weights and in their reactivities to monoclonal antibodies. The cloning and sequencing of the ospAB opérons from strains of different origins has demonstrated that the heterogeneity is found also at the DNA level Comparison of the ospAB sequences allows the classification of the strains into three types, which coincide with the recent species designations, B. burgdorferi sensu stricto, B. afzelii and B. garinii The genes are located on a linear plasmid about 50 kb in size, and are cotranscribed as a single message.

    The expression of the osp operon in different strains was studied by Western blot and Northern blot analysis. The ospAB operon of strains expressing varying amounts of the Osp proteins was cloned and sequenced. The DNA sequence was found to be >99% identical. The regulation appears to be primarily at the transcriptional level.

    In patients who have received incomplete treatment, B. burgdorferi have been isolated several years after the onset of the disease. As mentioned above, the ospAB loci of different strains show considerable heterogeneity, and it has been speculated that the spirochetes evade the host’s immune system by antigenic variation of the Osp proteins. In a mouse model system it was shown that no variation of the osp genes occurs over the course of an infection, and that other escape mechanisms must be used.

    The OspB proteins in particular have been shown to be very heterogeneous in different isolates. The MAb 84C recognizes a wide variety of B. burgdorferi strains, and the binding epitope was mapped to a conserved region in the carboxyl terminus of the OspB protein with putative structural and/or functional importance.

    It is well known that antibodies can kill bacteria in the presence of complement and phagocytes. Some antibodies seem to have a bactericidal effect by themselves. H6831 is a monoclonal antibody recognizing the OspB protein of some B. burgdorferi strains. The bactericidal action of univalent FAb fragments from H6831 was further characterized, and the binding epitope was mapped to a very heterogeneous region of the carboxyl end of the OspB protein.

  • 29.
    Jonsson, Maria
    et al.
    Umeå University, Faculty of Medicine, Microbiology.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Microbiology.
    Transcriptional and translational regulation of the expression of the major outer surface proteins in Lyme disease Borrelia strains1995In: Microbiology, ISSN 1350-0872, E-ISSN 1465-2080, Vol. 141, no 6, p. 1321-1329Article in journal (Refereed)
    Abstract [en]

    The major outer surface proteins of Lyme disease spirochaetes are differentially expressed in different isolates. Borrelia afzelii strain F1 expresses none, or very low amounts, of the OspA and OspB proteins. To elucidate the mechanisms that control the expression of these abundant surface proteins the ospAB operon of B. afzelii F1 was cloned, sequenced and compared to the previously sequenced ospAB operon of B. afzelii ACAI and Borrelia burgdorferi B31. The two B. afzelii strains showed almost 100% identity at the DNA level, although Coomassie-stained gels and Western blot analyses showed significant variation in the Osp protein content. Transcriptional analysis revealed that the amount of ospAB mRNA produced in B. afzelii F1 varies more than the amount of protein, suggesting that the expression of OspA and OspB proteins is regulated at both the transcriptional and the translational level. Furthermore, the inverse relationship between the transcription of ospC and the ospAB operon could indicate coregulation of these separately encoded operons.

  • 30.
    Jonsson, Maria
    et al.
    Umeå University, Faculty of Medicine, Microbiology.
    Elmros, Teodor
    Umeå University, Faculty of Medicine, Microbiology.
    Bergström, Sven
    Umeå University, Faculty of Medicine, Microbiology.
    Subcutaneous implanted chambers in different mouse strains as an animal model to study genetic stability during infection with Lyme disease Borrelia1995In: Microbial Pathogenesis, ISSN 0882-4010, E-ISSN 1096-1208, Vol. 18, no 2, p. 109-14Article in journal (Refereed)
    Abstract [en]

    Tissue metal net cages were implanted subcutaneously in BALB/cJ and C3H/Tif mice as an experimental model of Borrelia burgdorferi infection. B. burgdorferi sensu stricto strain Sh2-82 could be isolated up to 14 weeks after the inoculation. However, a significant difference in infectivity between the two mice strains was observed. C3H/Tif mice were more susceptible to developing chronic B. burgdorferi s.s. infections than BALB/cJ mice. Although a B. burgdorferi infection was established, no rearrangements in the ospA and ospB genes were observed in any of the infected mice.

  • 31. Jonsson, Maria
    et al.
    Noppa, L
    Barbour, A G
    Bergström, S
    Heterogeneity of outer membrane proteins in Borrelia burgdorferi: comparison of osp operons of three isolates of different geographic origins.1992In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 60, no 5, p. 1845-53Article in journal (Refereed)
    Abstract [en]

    Biochemical and immunochemical studies of the outer membrane proteins of Borrelia burgdorferi have shown that the OspA and OspB proteins from strains of different geographic origins may differ considerably in their reactivities with monoclonal antibodies and in their apparent molecular weights. To further characterize this variation in Osp proteins between strains, the osp operons and deduced translation products from two strains, one from Sweden (ACAI) and one from eastern Russia (Ip90), were studied. Polyacrylamide gel electrophoresis and Western blot (immunoblot) analyses confirmed differences between ACAI, Ip90, and the North American strain B31 in their Osp proteins. The sequences of the ospA and ospB genes of ACAI and Ip90 were compared with that of the previously studied osp operon of B31 (S. Bergström, V. G. Bundoc, and A. G. Barbour, Mol. Microbiol. 3:479-486, 1989). The osp genes of ACAI and Ip90, like the corresponding genes of B31, were found on plasmids with apparent sizes of about 50 kb and are cotranscribed as a single unit. Pairwise comparisons of the nucleotide sequences revealed that the ospA genes of ACAI and Ip90 were 85 and 86% identical, respectively, to the ospA gene of strain B31 and 86% identical to each other. The ospB sequences of these two strains were 79% identical to the ospB gene of B31 and 81% identical to each other. There was significantly greater similarity between the ospA genes of the three different strains than there was between the ospA and ospB genes within each strain. These studies suggest that the duplication of osp genes in B. burgdorferi occurred before the geographical dispersion of strains represented by ACAI, Ip90, and B31.

  • 32. Kaneko, Takanori
    et al.
    Murakami, Masamoto
    Kishibe, Mari
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Morhenn, Vera B
    Ishida-Yamamoto, Akemi
    Iizuka, Hajime
    Over-expression of kallikrein related peptidases in palmoplantar pustulosis.2012In: Journal of dermatological science (Amsterdam), ISSN 0923-1811, E-ISSN 1873-569X, Vol. 67, no 1, p. 73-76Article in journal (Refereed)
  • 33. Kasparek, Petr
    et al.
    Ileninova, Zuzana
    Zbodakova, Olga
    Kanchev, Ivan
    Benada, Oldrich
    Chalupsky, Karel
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Beck, Inken M.
    Sedlacek, Radislav
    KLK5 and KLK7 Ablation Fully Rescues Lethality of Netherton Syndrome-Like Phenotype2017In: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 1, article id e1006566Article in journal (Refereed)
    Abstract [en]

    Netherton syndrome (NS) is a severe skin disease caused by the loss of protease inhibitor LEKTI, which leads to the dysregulation of epidermal proteases and severe skin-barrier defects. KLK5 was proposed as a major protease in NS pathology, however its inactivation is not sufficient to rescue the lethal phenotype of LEKTI-deficient mice. In this study, we further elucidated the in vivo roles of the epidermal proteases in NS using a set of mouse models individually or simultaneously deficient for KLK5 and KLK7 on the genetic background of a novel NS-mouse model. We show that although the ablation of KLK5 or KLK7 is not sufficient to rescue the lethal effect of LEKTI-deficiency simultaneous deficiency of both KLKs completely rescues the epidermal barrier and the postnatal lethality allowing mice to reach adulthood with fully functional skin and normal hair growth. We report that not only KLK5 but also KLK7 plays an important role in the inflammation and defective differentiation in NS and KLK7 activity is not solely dependent on activation by KLK5. Altogether, these findings show that unregulated activities of KLK5 and KLK7 are responsible for NS development and both proteases should become targets for NS therapy.

  • 34.
    Lundwall, Åke
    et al.
    Malmö Allmänna sjukhus, Klinisk kemi.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Kalikrein-related peptidases2008In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 65, no 13, p. 2019-2038Article, review/survey (Refereed)
  • 35. Murakami, M.
    et al.
    Kaneko, T.
    Kishibe, M.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Morhenn, V.
    Ishida-Yamamoto, A.
    Iizuka, H.
    Shirakata, Y.
    Sayama, K.
    Multiple over-expression of kallikrein related peptidases contributes to the inflammatory hyperkeratotic change with abnormal desquamation in lesions of palmoplantar pustulosis2012In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 132, p. S62-S62Article in journal (Other academic)
  • 36.
    Stefansson, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Ny, Annelii
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Glas, Bo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Egelrud, Torbjörn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Kallikrein-related peptidase 14 may be a major contributor to trypsin-like proteolytic activity in human stratum corneum.2006In: Biological chemistry (Print), ISSN 1431-6730, E-ISSN 1437-4315, Vol. 387, no 6, p. 761-768Article in journal (Refereed)
  • 37.
    Stefansson, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Roosterman, Dirk
    Kempkes, Cordula
    Bocheva, Georgeta
    Steinhoff, Martin
    Egelrud, Torbjörn
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases2008In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 128, no 1, p. 18-25Article in journal (Refereed)
    Abstract [en]

    Proteinase-activated receptor-2 (PAR2) is a seven transmembrane spanning, G-protein-coupled receptor, present on the membrane of many cell types including keratinocytes. In skin, PAR2 is suggested to play a regulatory role during inflammation, epidermal barrier function, and pruritus. PAR2 is activated by trypsin-like proteases by a unique mechanism where cleavage of the receptor leads to the release of a small peptide, which activates the receptor as a tethered ligand. The endogenous activators of PAR2 on keratinocytes have not been identified as of yet. Potential candidates are kallikrein-related peptidases (KLKs) expressed by epidermal cells. Therefore, the ability of four human skin-derived KLKs was examined with regard to their capacity to activate PAR2 in vitro. PAR2 cleavage was followed by immunofluorescence analysis and functional activation by measurements of changes in intracellular calcium levels. We found that KLK5 and KLK14, but neither KLK7 nor KLK8, induced PAR2 signalling. We conclude that certain, but not all, epidermal KLKs are capable of activating PAR2. We could also show the coexpression of KLK14 and PAR2 receptor in inflammatory skin disorders. These in vitro results suggest that KLKs may take part in PAR2 activation in the epidermis and thereby in PAR2-mediated inflammatory responses, including epidermal barrier repair and pruritus. The role of KLKs in PAR2 activation in vivo remains to be elucidated.

1 - 37 of 37
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