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  • DKFZ Publication Database  (31)
  • KERATINOCYTES  (16)
  • MELANOMA  (15)
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  • DKFZ Publication Database  (31)
Keywords
  • 1
    Keywords: EXPRESSION ; IN-VITRO ; DISTINCT ; DIFFERENTIATION ; MESSENGER-RNA ; murine ; KERATINOCYTES ; EPIDERMAL DIFFERENTIATION ; ARACHIDONIC-ACID ; calcium gradient ; ENHANCING FACTOR ; epidermal barrier ; GROUP-II ; GROUP-V ; GROUP-X ; hyperproliferation ; INVITRO CULTIVATION ; LOW-MOLECULAR-WEIGHT ; neonatal mouse ; NEONATAL MOUSE KERATINOCYTES ; PERMEABILITY BARRIER HOMEOSTASIS ; epidermis
    Abstract: The action of secreted phospholipases A(2) in skin is thought to be essential for epidermal barrier homeostasis. The incomplete knowledge of presence and functions of the novel secreted phospholipase A(2) subtypes in skin prompted us to explore their expression in epidermis and primary keratinocytes from murine neonatal skin. We detected secreted phospholipases A(2) -IB, -IIA, -IIC, -IID, -IIE, -IIF, -V, -X, and -XII. To study secreted phospholipase A(2) expression during epidermal differentiation, primary keratinocytes from the basal, suprabasal, and upper differentiated layers of neonatal mouse epidermis were obtained by density gradient centrifugation. mRNA for secreted phospholipases A(2) -IB, -IIE, -IIF, -V, and -XII-1 are mainly expressed in the upper differentiated layers, whereas the most prominent enzymes in the basal and suprabasal layers are secreted phospholipases A(2) -IIA, -IID, and -X. The mRNA for secreted phospholipase A(2) -IIC was found in all fractions. Immunohistochemical analysis in mouse skin sections reflected the mRNA distribution patterns in the different epidermal cell fractions. After in vitro induction of keratinocyte differentiation by increasing the calcium concentration of the medium, secreted phospholipases A(2) -IB, -IIE, -IIF, -V, and -XII-1 were upregulated, whereas secreted phospholipases A(2) -IIA, -IIC, -IID, and -X were mainly expressed in proliferating keratinocytes. The specific secreted phospholipase A(2) expression profile in the skin suggests a distinct function for each enzyme in the epidermis
    Type of Publication: Journal article published
    PubMed ID: 12839576
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  • 2
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; INHIBITION ; DISTINCT ; GENE ; PROTEIN ; LINES ; DNA ; CELL-CYCLE ; IDENTIFICATION ; REPAIR ; MELANOMA ; MALIGNANT-MELANOMA ; CISPLATIN ; drug resistance ; ABCC2 ; MRP2 ; ANTICANCER DRUGS ; ACQUIRED DRUG-RESISTANCE ; cMOAT ; ETOPOSIDE ; FOTEMUSTINE ; MeWo
    Abstract: Resistance to various anti-neoplastic agents is a common observation in clinical management of melanoma. The biologic mechanisms conferring these different drug-resistant phenotypes, including resistance against the commonly used anti-cancer drug cisplatin, are unclear. In order to elucidate the role of the membrane adenosine triphosphate binding cassette-transporter cMOAT (canalicular multispecific anion transporter) (MRP2/ABCC2) in cisplatin resistance of melanoma, the expression of this protein was analyzed in the platinum drug-resistant cell line MeWo CIS 1. Cisplatinresistant melanoma cells showed a distinct overexpression of cMOAT on mRNA and protein level. This observation was accompanied by a reduced formation of platinum-induced intrastrand cross-links in the nuclear DNA measured by an immunocytologic assay. This decrease in DNA platination was accompanied by an accelerated re-entry into the cell cycle after the typical cisplatin- induced G(2) arrest, and a resistance to undergo apoptosis. Kinetics of formation and elimination of platinum-DNA adducts suggest that the DNA repair capacity for Pt-d(GpG) adducts was not elevated in platinum drug-resistant melanoma cells. The decrease in platinum-DNA adduct formation in cisplatin- resistant melanoma cells was rather a reflection of the protecting activity of the transporter cMOAT. In conclusion, the functional inhibition of cMOAT might be a promising strategy in the reversal of resistance to platinum-based anti- cancer drugs in human melanoma
    Type of Publication: Journal article published
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  • 3
    Keywords: CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; proliferation ; CELL ; CELL-PROLIFERATION ; Germany ; human ; GENERATION ; SYSTEM ; DISTINCT ; PROTEIN ; PROTEINS ; cell line ; LINES ; ACTIVATION ; RESPONSES ; REDUCTION ; KERATINOCYTES ; SKIN ; CELL-LINES ; ISOFORM ; SUBUNIT ; Western-blot ; MEMBRANE ; CELL-LINE ; LINE ; CYTOCHROME-C ; EPITHELIAL-CELLS ; PROTEIN LEVELS ; western blot ; HaCaT ; MUCOSA ; HOST-DEFENSE ; DEFENSE ; human skin and oral epithelial cells,oxidoreductase,p67phox,spin trapping,superoxide radical ; NAD(P)H OXIDASE ; OXYGEN RADICALS ; P47(PHOX) ; SUPEROXIDE-PRODUCTION
    Abstract: In non-phagocytic cells, superoxide has been implicated in physiological and pathological cellular functions in the skin and mucosa, such as, host defense, mitogenic responses, and malignant conversion. Here, we identify a constitutively expressed heme-flavoprotein NADPH oxidase (Nox) system as a source of superoxide in human skin (HaCaT) and gingival mucosal (GM16) keratinocyte cell lines. Western blot analysis showed that both cell lines expressed the phagocyte oxidase (phox) cytosolic proteins Rac1, p40phox, and p67phox. With respect to the catalytic flavoheme protein subunit, HaCaT membranes, which expressed p22phox, showed an absorbance peak at 558 nm indicative of a b-type cytochrome. At mRNA levels, both GM16 and HaCaT cells expressed gp91phox homologs Nox1, Nox2, and Nox4, however, HaCaT cells expressed very low levels of Nox1 mRNA. At protein levels, Nox1 was readily detected in HaCaT but was nearly undetectable in GM16 cells. Consistently, Nox activity of HaCaT membranes was demonstrated by electron paramagnetic resonance spin-trapping and cytochrome c reduction, and the activity was sensitive to the flavoprotein inhibitor diphenylene iodonium. V-max values were 20-fold lower than those reported for phagocytic oxidase. In conclusion, keratinocytes expressed a Nox distinct from the phox isoform of phagocytes providing molecular evidence for a source of superoxide that may regulate cell proliferation and host defense in skin and oral mucosa
    Type of Publication: Journal article published
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  • 4
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; Germany ; PROTEIN ; DRUG ; SKIN ; resistance ; inactivation ; MELANOMA ; CISPLATIN ; CUTANEOUS MELANOMA ; drug resistance ; DRUG-RESISTANCE ; ETOPOSIDE ; DEFICIENCY ; DEPENDENT APOPTOSIS ; 12Q22-23
    Type of Publication: Journal article published
    PubMed ID: 16098052
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  • 5
    Keywords: CANCER CELLS ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; CLINICAL-TRIAL ; COMBINATION ; evaluation ; Germany ; human ; IN-VIVO ; MODEL ; THERAPY ; NEW-YORK ; EFFICIENCY ; TRANSDUCTION ; primary ; prognosis ; DOMAIN ; culture ; GLYCOPROTEIN ; virus ; TRIAL ; TRIALS ; VECTORS ; VECTOR ; MEMBRANE ; CLINICAL-TRIALS ; chemotherapy ; EFFICIENT ; MELANOMA ; MALIGNANT-MELANOMA ; malignant melanoma ; CUTANEOUS MELANOMA ; ADENOVIRUS ; DACARBAZINE ; DOMAINS ; THERAPIES ; MELANOMA-CELLS ; VIROTHERAPY ; USA ; EFFICIENT TRANSDUCTION ; SHORT-TERM ; xenograft ; clinical trial ; ONCOLYTIC ADENOVIRUSES ; B ADENOVIRUSES ; CELLULAR RECEPTOR ; FUSOGENIC MEMBRANE-GLYCOPROTEINS ; REPLICATING ADENOVIRUS ; SUICIDE GENE-THERAPY ; ADENOVIRUS VECTORS ; IMMUNE-MEDIATED CONTROL ; oncolytic adenovirus
    Abstract: Advanced melanoma is associated with poor prognosis warranting the development of new therapeutics, such as oncolytic adenoviruses for immunovirotherapy. Since this approach critically depends on efficient transduction of targeted tumor cells, we screened a panel of 22 different adenovirus types for their internalization efficiency in melanoma cells. We demonstrated that the virions of Ad35, Ad38, and Ad3 have significantly higher internalization efficiency in melanoma cells than Ad5, so far the only adenovirus type used in clinical trials for melanoma. Therefore, we developed a conditionally replication-competent Ad5-based vector with the Ad35 fiber shaft and knob domains (Ad5/35) and compared its therapeutic efficacy with the homologous vector carrying the native Ad5 fiber. To further enhance virotherapy, we combined the oncolytic adenovirus vectors with intratumoral expression of measles virus fusogenic membrane glycoproteins H and F (MV-H/F) and dacarbazine chemotherapy. In a human melanoma xenograft model, established from a short-term culture of primary melanoma cells, we demonstrated that the Ad5/35-based therapy had a significantly greater anti-neoplastic effect than the homologous Ad5-based therapy. Furthermore, the combination of virotherapy, intratumoral expression of MV-H/F, and chemotherapy was clearly superior to single- or double-agent therapy. In conclusion, Ad35-based vectors are promising for the treatment of melanoma
    Type of Publication: Journal article published
    PubMed ID: 17960177
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  • 6
    Keywords: CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; proliferation ; SURVIVAL ; CELL ; CELL-PROLIFERATION ; Germany ; IN-VIVO ; VIVO ; microarray ; RNA ; ADHESION MOLECULES ; MOLECULES ; TISSUE ; SUPPRESSION ; BREAST-CANCER ; TARGET ; CELL-SURVIVAL ; PROGRESSION ; METASTASIS ; MELANOMA ; ADHESION ; MIGRATION ; EPITHELIAL-CELLS ; L1 ; MALIGNANT-MELANOMA ; TARGETS ; CELL-ADHESION MOLECULE ; OVEREXPRESSION ; DIFFERENTIAL EXPRESSION ; AMYLOID PRECURSOR PROTEIN ; chemoresistance ; CELL-GROWTH ; E-cadherin ; development ; tissue microarray ; ALPHA-SECRETASE
    Abstract: ADAM10 (a disintegrin and metalloproteinase 10) is involved in the ectodomain shedding of various substrates, including adhesion molecules such as L1 cell adhesion molecule (L1-CAM) and CD44, which are known to have important roles in the development of malignant melanoma. In our Study, we characterized the expression of ADAM10 in melanoma cells in vitro and in vivo Immunohistochemical analysis oil tissue microarrays indicated that ADAM-10 expression was significantly elevated in melanoma metastasis compared with primary melanomas. In vitro downregulation of ADAM10 with specific small interfering RNA (siRNA) resulted in a suppression of the anchorage-independent cell growth and reduced the migration of melanoma cells. In addition, overexpression of ADAM-10 induced the migration of melanoma cells. In cell lines from melanoma patients with metastasis, ADAM10 was significantly overexpressed, and ADAM10 expression correlated with increased cell proliferation. Furthermore, we present evidence that ADAM-10 is involved in the release of L1-CAM from melanoma cells. It is important that knockdown of cellular L1-CAM reduced the migration of melanoma cells and abrogated the chemoresistance against cisplatin. In contrast, soluble L1-CAM had no effect on melanoma cell migration or cell survival. Taken together, Our data demonstrate that ADAM10 and L1-CAM have important roles during melanoma progression and both molecules represent attractive targets for therapeutical intervention of melanomas
    Type of Publication: Journal article published
    PubMed ID: 19865098
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  • 7
    Keywords: CELLS ; ACTIVATION ; KERATINOCYTES ; SKIN ; CYCLE ; MIGRATION ; E6 ; E-cadherin ; EPIDERMODYSPLASIA-VERRUCIFORMIS ; LIFE ; DNA LOADS
    Abstract: Human papillomaviruses (HPVs), which are contained in the alpha, beta, gamma, mu, and nu genera, differ in their oncogenic potential and their tropism for cutaneous or mucosal epidermis. Langerhans cells (LC), the only epidermal professional antigen-presenting cells, are readily detected in normal mucosal and cutaneous epithelium. The aim of this study is to determine whether LC loss, which has been reported for HPV16, occurs in other HPV genera and establish its significance in viral pathology. We found that, as for HPV16, LCs were reduced in lesions infected with high-risk mucosal (alpha 7 and alpha 9 species) and low-risk cutaneous (gamma and mu) types. Lesions infected with alpha 10 low-risk genital types had reduced LC but contained epidermal LC patches, coincident with dermis-localized regulatory T cells (T-regs). In contrast to other genera, LCs were common in the epidermis, and T-regs occupied the dermis of the potentially high-risk cutaneous beta-HPV type infected lesions. Therefore, LC loss in the infected lesions occurred irrespective of tropism or oncogenic potential of the HPV type. LC depletion in the HPV-infected epidermis may create an environment that is permissive for viral persistence and in HPV lesions in which LCs are found, the presence of typically immunosuppressive T-regs may compensate for their continued presence
    Type of Publication: Journal article published
    PubMed ID: 19759549
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  • 8
    Keywords: EXPRESSION ; AGENTS ; human ; GENE ; PROTEIN ; DIFFERENTIATION ; TISSUE ; MICE ; MECHANISM ; INDUCTION ; TISSUES ; KERATINOCYTES ; mechanisms ; SKIN ; SEQUENCE ; SEQUENCES ; STAGE ; TRANSGENIC MICE ; IDENTIFICATION ; PROMOTER ; transgenic ; REGION ; FRANCE ; hyperproliferation ; epidermis ; TERMINAL DIFFERENTIATION ; LAYER ; MAMMALIAN-TISSUES ; HASSALLS CORPUSCLES ; FOLLICLE ; HAIR-FOLLICLES ; HUMAN TISSUES ; INNER-ROOT-SHEATH ; AGENT ; PATTERN ; HAIR FOLLICLE ; corneodesmosin ; CORNIFIED EPITHELIA ; GENE PROMOTER ; hyperkeratosis ; KERATINOCYTE DIFFERENTIATION ; promoter regions ; PSORIASIS SUSCEPTIBILITY ; REPORTER GENE ; S GENE ; STRATUM-CORNEUM
    Abstract: Corneodesmosin (CDSN) is a desmosomal protein expressed in the epidermis during the late stages of differentiation and in the inner root sheath of hair follicles. The homophilic adhesive properties of the protein suggest that it reinforces keratinocyte cohesion in the upper layers of the epidermis (stratum granulosum and stratum corneum). In this study, we analyzed the expression of the CDSN gene in 16 human tissues. We confirmed the closely restricted expression pattern of CSDN. Indeed, apart from the skin, the mRNA was significantly detected only in the placenta and the thymus. As a step in elucidating the mechanisms of tissue-specific expression, transgenic mice bearing a 4.2 kb fragment of the human CSDN gene promoter linked to the LacZ gene were generated. The reporter-gene expression was detected in special areas of the inner root sheath of the hair follicles and the hair medulla but not in the epidermis. Induction of epidermis hyperproliferation however either by pharmacological agents or by wounding led to strong expression of the reporter gene in the keratinocytes of the stratum granulosum and the parakeratotic corneocytes of the stratum corneum. The data suggest that the genomic sequences and/or regulating factors responsible for the cell-specific expression of the human CDSN gene in the normal hair follicle as well as in the hyperproliferative epidermis are different from those necessary for expression in the normal epidermis
    Type of Publication: Journal article published
    PubMed ID: 15086560
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  • 9
    Keywords: ANGIOGENESIS ; CANCER ; EXPRESSION ; INVASION ; proliferation ; SURVIVAL ; tumor ; CELL-PROLIFERATION ; MICROVESSEL DENSITY ; DENSITY ; GENE ; GENES ; TUMORS ; PATIENT ; ACTIVATION ; FAMILY ; prognosis ; PROGRESSION ; MUTATION ; metastases ; MELANOMA ; MUTATIONS ; ONCOGENE ; CHILDREN ; CUTANEOUS MELANOMA ; INITIATION ; BRAF ; N-RAS ; Ras ; neuroblastoma ; RE ; PATIENT SURVIVAL ; cell proliferation ; CODON ; CUTANEOUS MELANOMAS ; Ki-67 ; NEVI ; RAS MUTATIONS ; VERTICAL GROWTH-PHASE
    Abstract: Previous studies have shown frequent mutations in the BRAF (V-raf murine sarcoma viral oncogene homolog B1) or NRAS ( neuroblastoma RAS viral [V-ras] oncogene homolog) genes in cutaneous melanoma, but the relationship between these alterations and tumor cell proliferation has not been examined in human melanoma. In our study of 51 primary nodular melanomas and 18 paired metastases, we found mutations in BRAF ( codon 600, previously denoted 599) in 15 primary tumors (29%) and eight metastases (44%). The figures for NRAS mutations were 27% and 22%, respectively. Mutations in BRAF and NRAS genes were mutually exclusive in all but one case, and were maintained from primary tumors through their metastases. Mutations, however, were not associated with tumor cell proliferation by Ki-67 expression, tumor thickness, microvessel density, or vascular invasion, and there were no differences in patient survival. Although BRAF and NRAS mutations are likely to be important for the initiation and maintenance of some melanomas, other factors might be more significant for proliferation and prognosis in subgroups of aggressive melanoma
    Type of Publication: Journal article published
    PubMed ID: 16098042
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  • 10
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; INVASION ; tumor ; TUMOR-CELLS ; Germany ; VITRO ; SYSTEM ; SYSTEMS ; ENZYMES ; TISSUE ; MECHANISM ; FAMILY ; INDUCTION ; mechanisms ; fibroblasts ; ALPHA ; antibodies ; antibody ; PROGRESSION ; METASTASIS ; NUDE-MICE ; MELANOMA ; DEGRADATION ; ANTAGONIST ; HUMAN DERMAL FIBROBLASTS ; MATRIX ; TUMOR INVASION ; collagen ; MATRIX METALLOPROTEINASES ; MELANOMA-CELLS ; TUMORIGENICITY ; regulation ; interaction ; basic fibroblast growth factor ; bFGF ; dermal fibroblasts ; IL-1 alpha ; MALIGNANT MELANOMAS ; TIMP-1 ; TISSUE INHIBITOR
    Abstract: Tumor invasion and metastasis of melanoma have been shown to require proteolytic degradation of the extracellular environment, achieved primarily by enzymes of the matrix metalloproteinases (MMP) family. Increased enzyme activity is localized at the border of tumor cells and the adjacent peritumoral connective tissue, emphasizing the crucial role of tumor-stroma interactions in the regulation of MMP activity. To analyze whether direct cell-cell contacts of melanoma cells and stromal fibroblasts or whether soluble factors, secreted by melanoma cells are involved in the regulation of MMP, we used different in vitro co-culture systems. Both direct and indirect co-cultures of high invasive BLM melanoma cells and human dermal fibroblasts resulted in an induction of pro-MMP-1 synthesis. Medium conditioned by BLM cells strongly induced pro-MMP-1 synthesis in fibroblasts, indicating the importance of diffusible factors for this induction. Competition by recombinant human interleukin (IL)-1 receptor antagonist, neutralizing IL-1alpha and basic fibroblast growth factor (bFGF) antibodies, resulted in a concentration-dependent reduction of pro-MMP-1 synthesis. Taken together, our results indicate an essential role for soluble factors, mainly IL-1alpha and bFGF, in the stimulation of dermal fibroblasts by human melanoma cells to secrete MMP-1
    Type of Publication: Journal article published
    PubMed ID: 15737206
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