8 results on '"Ulpu Saarialho-Kere"'
Search Results
2. The PSORS1 locus gene CCHCR1 affects keratinocyte proliferation in transgenic mice
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Björn Rozell, Ulpu Saarialho-Kere, Sari Suomela, Janica Wakkinen, Outi Elomaa, Raija Tammi, Inkeri Tiala, Kati Kainu, Sofi Forsberg, Pauli Puolakkainen, Juha Kere, and Ola Rollman
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Keratinocytes ,Genetically modified mouse ,Candidate gene ,Transgene ,Mice, Transgenic ,CCHCR1 Gene ,Biology ,Mice ,Downregulation and upregulation ,Cell Movement ,Genetics ,medicine ,Animals ,Psoriasis ,Allele ,Molecular Biology ,Genetics (clinical) ,Cell Proliferation ,Wound Healing ,Hyperplasia ,integumentary system ,Intracellular Signaling Peptides and Proteins ,General Medicine ,Molecular biology ,CCHCR1 ,medicine.anatomical_structure ,Tetradecanoylphorbol Acetate ,Keratinocyte - Abstract
The CCHCR1 gene (Coiled-Coil alpha-Helical Rod protein 1) within the major psoriasis susceptibility locus PSORS1 is a plausible candidate gene for the risk effect. We have previously generated transgenic mice overexpressing either the psoriasis-associated risk allele CCHCR1*WWCC or the normal allele of CCHCR1. All transgenic CCHCR1 mice appeared phenotypically normal, but exhibited altered expression of genes relevant to the pathogenesis of psoriasis, including upregulation of hyperproliferation markers keratins 6, 16 and 17. Here, we challenged the skin of CCHCR1 transgenic mice with wounding or 12-O-tetradecanoyl-13-acetate (TPA), treatments able to induce epidermal hyperplasia and proliferation that both are hallmarks of psoriasis. These experiments revealed that CCHCR1 regulates keratinocyte proliferation. Early wound healing on days 1 and 4 was delayed, and TPA-induced epidermal hyperproliferation was less pronounced in mice with the CCHCR1*WWCC risk allele than in mice with the normal allele or in wild-type animals. Finally, we demonstrated that overexpression of CCHCR1 affects basal keratinocyte proliferation in mice; CCHCR1*WWCC mice had less proliferating keratinocytes than the non-risk allele mice. Similarly, keratinocytes isolated from risk allele mice proliferated more slowly in culture than wild-type cells when measured by BrdU labeling and ELISA. Our data show that CCHCR1 may function as a negative regulator of keratinocyte proliferation. Thus, aberrant function of CCHCR1 may lead to abnormal keratinocyte proliferation which is a key feature of psoriatic epidermis.
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- 2007
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3. Downstream target genes of the neuropeptide S–NPSR1 pathway
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Ulpu Saarialho-Kere, Johanna Vendelin, Sara Bruce, Juha Kere, Tari Haahtela, P. Holopainen, Asta Pirskanen, Paula Rytilä, Marko Rehn, Lauri A. Laitinen, Ville Pulkkinen, Tarja Laitinen, and Annika Laitinen
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MMP10 ,Apoptosis ,Bronchi ,Biology ,Cell Line ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,0302 clinical medicine ,Matrix Metalloproteinase 10 ,Databases, Genetic ,Neuropeptide S ,Genetics ,Humans ,Receptor ,Molecular Biology ,Gene ,Genetics (clinical) ,Cell Proliferation ,DNA Primers ,Oligonucleotide Array Sequence Analysis ,030304 developmental biology ,Tissue Inhibitor of Metalloproteinase-3 ,0303 health sciences ,Base Sequence ,Microarray analysis techniques ,Neuropeptides ,Metalloendopeptidases ,General Medicine ,EPH receptor A2 ,Molecular biology ,Asthma ,3. Good health ,Nuclear receptor ,030220 oncology & carcinogenesis ,Signal transduction ,Signal Transduction - Abstract
The neuropeptide S (NPS)-NPS receptor 1 (NPSR1) pathway has recently been implicated in the pathogenesis of asthma. The purpose of this study was to identify downstream gene targets regulated by NPSR1 upon NPS stimulation. A total of 104 genes were found significantly up-regulated and 42 down-regulated by microarray analysis 6 h after NPS administration. By Gene Ontology enrichment analysis, the categories 'cell proliferation', 'morphogenesis' and 'immune response' were among the most altered. A TMM microarray database comparison suggested a common co-regulated pathway, which includes JUN/FOS oncogene homologs, early growth response genes, nuclear receptor subfamily 4 members and dual specificity phosphatases. The expression of four up-regulated genes, matrix metallopeptidase 10 (MMP10), INHBA (activin A), interleukin 8 (IL8) and EPH receptor A2 (EPHA2), exhibited a significant NPS dose-response relationship as confirmed by quantitative reverse-transcriptase-PCR and for MMP10 by immunoassay. Immunohistochemical analyses revealed that MMP10 and TIMP metallopeptidase inhibitor 3 (TIMP3) were both strongly expressed in bronchial epithelium, and macrophages and eosinophils expressed MMP10 in asthmatic sputum samples. Because remodeling of airway epithelium is a feature of chronic asthma, the up-regulation of MMP10 and TIMP3 by NPS-NPSR1 signaling may be of relevance in the pathogenesis of asthma.
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- 2006
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4. Expression of matrix metalloproteinase (MMP)-7 and MMP-13 and loss of MMP-19 and p16 are associated with malignant progression in chronic wounds
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Syrjänen S, Leila Jeskanen, Laura Ravanti, Baldursson B, Ulla Impola, Ulpu Saarialho-Kere, and Veli-Matti Kähäri
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Pathology ,medicine.medical_specialty ,Skin Neoplasms ,Pseudoepitheliomatous Hyperplasia ,Dermatology ,Biology ,Matrix metalloproteinase ,medicine.disease_cause ,Malignant transformation ,Diagnosis, Differential ,Matrix Metalloproteinase 12 ,Matrix Metalloproteinase 13 ,Matrix Metalloproteinases, Secreted ,medicine ,Carcinoma ,Humans ,Collagenases ,Cyclin-Dependent Kinase Inhibitor p16 ,In Situ Hybridization ,Aged ,Leg Ulcer ,Metalloendopeptidases ,medicine.disease ,Immunohistochemistry ,Matrix Metalloproteinases ,Epithelium ,stomatognathic diseases ,Matrix Metalloproteinase 8 ,medicine.anatomical_structure ,Epidermoid carcinoma ,Gelatinases ,Matrix Metalloproteinase 7 ,Chronic Disease ,Carcinoma, Squamous Cell ,Matrix Metalloproteinase 3 ,Carcinogenesis - Abstract
Summary Background The risk of squamous cell carcinoma (SCC) is significantly increased in chronic leg ulcers. Very little is known about the molecular pathogenesis of these tumours, which are often undiagnosed for a long time. As matrix metalloproteinases (MMPs) are implicated at all stages of tumorigenesis, we investigated whether the pattern of epithelial MMP expression can predict development of SCC from pseudoepitheliomatous hyperplasia of chronic wounds. Methods Samples from nine patients with SCCs that had arisen in chronic wounds and 31 with venous leg ulcers were studied using immunohistochemistry for MMP-7, MMP-8, MMP-9, MMP-13, MMP-19 and the tumour suppressor p16. In situ hybridization was performed for MMP-1, MMP-3, MMP-7, MMP-12 and MMP-13. Results MMP-7 was expressed by malignantly transformed epithelium, while it was absent from chronic wounds. MMP-9 was detected in the epithelium in both SCCs and chronic wounds. Epithelial MMP-13 expression was strong in SCC, but was absent in chronic wounds. MMP-12 was expressed in the epithelium in two SCCs, while macrophages were positive in chronic wounds. MMP-19 was induced in proliferating epithelium of wounds, but was absent from invasive areas of SCC. p16 was expressed by keratinocytes in half of the chronic wounds and at superficial margins of SCCs, while invasive areas were negative. Conclusions Our results suggest that epithelial expression of MMP-7, MMP-12 and MMP-13, but not that of MMP-1, MMP-3, MMP-8, MMP-9 and MMP-10, in chronic wounds provides a diagnostic clue for distinguishing SCCs from nonmalignant wounds. The loss of MMP-19 and p16 from the epithelium could aid in making the differential diagnosis between well-differentiated SCCs and nonmalignant chronic wounds.
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- 2005
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5. Transgenic mouse models support HCR as an effector gene in the PSORS1 locus
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Hong Jiao, Juha Kere, Inkeri Majuri, Björn Rozell, Outi Elomaa, Johanna Pispa, Ulpu Saarialho-Kere, Zahra Mirzaei, Kati Asumalahti, Sari Suomela, and Karin Dahlman-Wright
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Candidate gene ,Linkage disequilibrium ,Transgene ,Gene Expression ,Mice, Transgenic ,Locus (genetics) ,Biology ,Mice ,Gene expression ,Genetics ,Genetic predisposition ,Animals ,Cluster Analysis ,Humans ,Psoriasis ,Genetic Predisposition to Disease ,Allele ,Molecular Biology ,Gene ,Genetics (clinical) ,Skin ,Reverse Transcriptase Polymerase Chain Reaction ,Intracellular Signaling Peptides and Proteins ,Proteins ,General Medicine ,Immunohistochemistry ,Molecular biology ,Disease Models, Animal ,Multigene Family ,human activities - Abstract
Genetic susceptibility for psoriasis is regulated to the greatest extent by the PSORS1 locus. Three psoriasis-associated susceptibility alleles have been identified within it, namely, HLACw6, HCR*WWCC and CDSN*5, but strong linkage disequilibrium between them has made it difficult to distinguish their individual genetic effects, and animal models to study their effects are not known. To study the function of HCR, we engineered transgenic mice with either a non-risk allele of HCR or the HCR*WWCC risk allele under the control of the cytokeratin-14 promoter. These choices were motivated by the apparently dominant effect of PSORS1 on psoriasis susceptibility and the physiological expression of HCR in basal keratinocytes. Transgenic mice appeared phenotypically normal and histologically their skin was indistinguishable from wild-type mice. Expression studies using Affymetrix arrays suggested that the HCR risk allele has specific functional consequences relevant to the pathogenesis of psoriasis. Comparison of gene expression changes between non-risk and risk allele mice revealed similarities to previous observations in human psoriatic skin, including upregulation of cytokeratins 6, 16 and 17 in risk allele mice. We also observed changes in the expression of genes associated with terminal differentiation and formation of the cornified cell envelope. Our results support the concept that HCR may constitute an essential gene in the PSORS1 locus. These observations are also compatible with a model that a susceptibility gene for psoriasis induces changes that are contributory but not sufficient by itself to produce the clinical phenotype.
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- 2004
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6. Coding haplotype analysis supports HCR as the putative susceptibility gene for psoriasis at the MHC PSORS1 locus
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Francesca Capon, Richard C. Trembath, Colin Veal, Michael Moser, Jonathan Barker, Sari Suomela, Ulpu Saarialho-Kere, Conxi Lázaro, Michael H. Allen, Tarja Laitinen, Kati Asumalahti, Samuli Ripatti, Outi Elomaa, Xavier Estivill, Giuseppe Novelli, Jan A. Marcusson, Hidemi Nakagawa, Juha Kere, Igor Vorechovsky, and Rafael de Cid
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Male ,Linkage disequilibrium ,Genotype ,Single-nucleotide polymorphism ,Locus (genetics) ,HLA-C Antigens ,Biology ,Linkage Disequilibrium ,030207 dermatology & venereal diseases ,03 medical and health sciences ,HLA-C ,0302 clinical medicine ,Genetics ,Humans ,Psoriasis ,Genetic Predisposition to Disease ,Amino Acid Sequence ,Age of Onset ,Allele ,Molecular Biology ,Gene ,Alleles ,Genetics (clinical) ,Glycoproteins ,030304 developmental biology ,Genetic association ,0303 health sciences ,Polymorphism, Genetic ,Haplotype ,Intracellular Signaling Peptides and Proteins ,Chromosome Mapping ,Genetic Variation ,Proteins ,Exons ,General Medicine ,Pedigree ,3. Good health ,Haplotypes ,Case-Control Studies ,Female ,human activities - Abstract
PSORS1, near HLA-C, is the major genetic determinant of psoriasis. We present genetic and structural evidence suggesting a major role for the HCR gene at the PSORS1 locus. Genotyping of 419 families from six populations revealed that coding single-nucleotide polymorphisms of HCR formed a conserved allele HCR*WWCC that associated highly significantly with psoriasis and with the HLA-Cw6 allele in all populations. Because of strong linkage disequilibrium between HLA-Cw6 and HCR*WWCC, the two genes could not be genetically distinguished by this sample size. However, the variant HCR allele was predicted to differ in secondary structure from the wild-type protein. HCR protein expression in lesional psoriatic skin differed considerably from that observed in normal skin. These results provide strong evidence for the HCR*WWCC allele as a major genetic determinant for psoriasis, probably by a mechanism impacting on keratinocyte proliferation.
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- 2002
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7. Ultrastructural features resembling those of harlequin ichthyosis in patients with severe congenital ichthyosiform erythroderma
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Ulpu Saarialho-Kere, Kirsti-Maria Niemi, Agneta Ganemo, Anders Vahlquist, Juha Kere, and E. Virolainen
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Adult ,Male ,medicine.medical_specialty ,Pathology ,Congenital ichthyosiform erythroderma ,Adolescent ,Erythroderma ,Dermatology ,Biology ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Congenital ichthyosis ,medicine ,Humans ,Child ,Skin ,030304 developmental biology ,0303 health sciences ,Ichthyosis ,Ectropion ,Ichthyosiform Erythroderma, Congenital ,Middle Aged ,Harlequin Ichthyosis ,Lamellar ichthyosis ,medicine.disease ,Dyskeratosis ,3. Good health ,Microscopy, Electron ,Child, Preschool ,Female ,Ichthyosis, Lamellar - Abstract
Congenital ichthyoses are a group of heterogeneous disorders of cornification. Autosomal recessive congenital ichthyosis (ARCI) can be clinically subdivided into congenital ichthyosiform erythroderma and lamellar ichthyosis. Ultrastructurally, ARCI is classified into four groups: ichthyosis congenita (IC) types I-IV. The genetic background of the ARCI disorders is heterogeneous, but only one disease gene, transglutaminase 1, has been detected so far. We describe six patients with severe congenital ichthyosis from six different Scandinavian families. They could not be classified ultrastructurally into the four IC groups because of atypical findings of electron microscopy. These included abnormal lamellar bodies, alterations in keratohyalin, remnant organelles and lipid inclusions in the upper epidermal cells, which resembled the ultrastructural findings of harlequin ichthyosis (HI), although the HI phenotype was not present at birth. Some clinical features, such as thick scales, erythroderma, alopecia and ectropion were common to all patients. Ichthyosis was usually accentuated in the scalp and four patients had clumped fingers and toes. None of the patients carried the transglutaminase 1 mutation. We conclude that ultrastructural findings resembling those detected in previous HI cases (type 1 and 2) can also be found in patients who do not have classic clinical features of that rare ichthyosis. This may be due to lack of specificity of ultrastructural markers for HI or to its clinical heterogeneity.
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- 2001
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8. Patterns of matrix metalloproteinase and TIMP-1 expression in chronic and normally healing human cutaneous wounds
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J. Lauharanta, Juha Kere, Ulpu Saarialho-Kere, Maarit Vaalamo, Pia Saarinen, Pauli Puolakkainen, and M Weckroth
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Chronic wound ,Pathology ,medicine.medical_specialty ,0303 health sciences ,integumentary system ,Matrix metalloproteinase inhibitor ,Surgical wound ,Inflammation ,In situ hybridization ,Dermatology ,Biology ,Matrix metalloproteinase ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,medicine ,Collagenase ,Matrilysin ,medicine.symptom ,medicine.drug ,030304 developmental biology - Abstract
The present study was carried out to characterize the patterns of expression of matrix metalloproteinases or their tissue inhibitor (TIMP-1) in normally healing, acute vs. chronic, skin wounds. In situ hybridization was performed to localize collagenase, stromelysin-1, stromelysin-2, matrilysin, urokinase plasminogen activator (uPA) and TIMP-1 mRNAs in 14 chronic venous ulcers and 10 normally healing wounds, representing different time points after wounding. Surgical wounds, made in piglets harvested at several time points, were studied as controls. Collagenase, stromelysin-1 and -2, as well as uPa, were expressed in keratinocytes in both acute and chronic wounds, while epithelial TIMP-1 mRNA was not detected in any chronic wound biopsies studied. However, TIMP-1 was expressed at the epithelial edges of both acute human and pig wounds. Our results suggest that the balance between metalloenzymes and their inhibitor TIMP-1, is disturbed, in poorly healing wounds.
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- 1996
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