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  • 1
    Keywords: CELLS ; EXPRESSION ; CELL ; Germany ; human ; INHIBITION ; PROTEIN ; PROTEINS ; DIFFERENTIATION ; COMPLEX ; COMPLEXES ; MECHANISM ; REDUCTION ; mechanisms ; BIOLOGY ; CELL-LINES ; treatment ; culture ; LINE ; CATALYTIC SUBUNIT GENE ; INTERMEDIATE-FILAMENTS ; CALCIUM ; DECLINE ; epidermis ; REGULATOR ; CALCIUM-BINDING PROTEIN ; MOLECULAR-MECHANISM ; RE ; keratinocyte ; SKIN KERATINOCYTES ; INCREASE ; INHIBIT ; INCREASES ; EXTRACELLULAR CALCIUM ; ION-BINDING PROPERTIES ; ULTRASTRUCTURAL-LOCALIZATION
    Abstract: Recently we reported a differentiation-dependent inhibition of telomerase activity in human epidermis. Consistent with this observation we found that in keratinocyte cultures calcium-induced differentiation correlates with a decline in telomerase activity. To get further support for a role of calcium in the regulation of telomerase and to elucidate the underlying molecular mechanisms we investigated the effect of calcium on telomerase in the human epidermal keratinocyte line HaCaT. Treatment with thapsigargin, which increases intracellular calcium concentrations, inhibited telomerase activity without down-regulating the expression of hTERT (human telomerase reverse transcriptase). This observation together with the fact that increasing calcium reduced telomerase activity in cell-free extracts suggests that calcium directly interacts with the telomerase complex. This interaction could be mediated by the calcium-binding protein S100A8 as indicated by its ability to mimic the inhibitory effect of calcium. S100A8-induced reduction in telomerase activity was abrogated by S100A9. The ratio of both proteins remained constant in cells treated with thapsigargin, but their interactions were altered similarly in intact cells after thapsigargin treatment and in cell-free extracts in response to calcium. We hypothesize that calcium binds to S100A8/S100A9 complexes and alters their composition, thus enabling S100A8 to interact with the telomerase complex and inhibit its activity
    Type of Publication: Journal article published
    PubMed ID: 17197440
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  • 2
    Keywords: APOPTOSIS ; CELLS ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; proliferation ; CELL ; IN-VIVO ; VITRO ; VIVO ; GENE ; GENES ; PROTEIN ; PROTEINS ; transcription ; cell line ; DIFFERENTIATION ; EPITHELIA ; LINES ; MECHANISM ; FAMILY ; TRANSCRIPTION FACTOR ; KERATINOCYTES ; mechanisms ; SKIN ; BIOLOGY ; CELL-LINES ; MEMBER ; culture ; TARGET ; TRANSCRIPTION FACTORS ; ENCODES ; genetics ; CELL-LINE ; LINE ; BETA ; ONCOGENE ; EPITHELIAL-CELLS ; GROWTH-FACTOR-BETA ; TARGETS ; cell lines ; epidermis ; heredity ; REGULATOR ; MORPHOGENESIS ; ONCOLOGY ; FAMILIES ; WOUND REPAIR ; FUNCTIONAL-CHARACTERIZATION ; TGF-BETA ; TGF-beta 1 ; SWITZERLAND ; LEVEL ; TARGET GENES ; EPITHELIUM ; function ; in vivo ; wound ; TRANSFORMING-GROWTH-FACTOR ; activin ; BINDING PROTEINS ; BONE MORPHOGENETIC PROTEIN ; KERATINOCYTE CELL-LINE ; LOOP-HELIX PROTEINS ; TRANSGENIC MICE REVEALS
    Abstract: Activin is a member of the transforming growth factor beta (TGF-beta) family, which plays a crucial role in skin morphogenesis and wound healing. To gain insight into the underlying mechanisms of action, we searched for activin-regulated genes in cultured keratinocytes. One of the identified target genes encodes Id1, a negative regulator of helix-loop-helix transcription factors. We show that Id1, Id2, and Id3 are strongly downregulated by activin in keratinocytes in vitro and in vivo. To determine the role of Id1 in keratinocyte biology, we generated stable HaCaT keratinocyte cell lines overexpressing this protein. Our results revealed that enhanced levels of Id1 do not affect proliferation of keratinocytes in monoculture under exponential culture conditions or in response to activin or TGF-beta 1. However, in three-dimensional organotypic cultures, Id1-overexpressing HaCaT cells formed a hyperthickened and disorganized epithelium that was characterized by enhanced keratinocyte proliferation, abnormal differentiation, and an increased rate of apoptosis. These results identify an important function of Id1 in the regulation of epidermal homeostasis
    Type of Publication: Journal article published
    PubMed ID: 16288215
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  • 3
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; proliferation ; tumor ; CELL ; KINASE ; DISEASE ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; DIFFERENTIATION ; LINES ; PATIENT ; SKIN ; CELL-LINES ; REPAIR ; CELL-LINE ; OVEREXPRESSION ; ORGANIZATION ; epidermis ; REGULATOR ; KERATINOCYTE GROWTH-FACTOR ; PSORIASIS ; keratinocyte ; LEVEL ; ROLES ; TGF-ALPHA ; NM23 ; NUCLEOSIDE DIPHOSPHATE KINASE ; wound healing
    Abstract: Keratinocyte growth factor (KGF) is an important regulator of epidermal homeostasis and repair. Therefore, the identification of KGF target genes in keratinocytes should contribute to our understanding of the molecular mechanisms underlying these processes. In a search for KGF-regulated genes, we identified the gene encoding the nucleoside diphosphate kinase NM23-H1. Apart from a housekeeping function, NM23 proteins are involved in the regulation of many cellular processes as well as in tumor metastasis, but their functions in epidermal homeostasis and repair are largely unknown. Here, we show a high expression of NM23-H1 and NM23-H2 in the KGF-responsive keratinocytes of the hyperprotiferative epidermis of mouse skin wounds and of patients suffering from the skin disease psoriasis. To determine if this overexpression is functionally important, we generated HaCaT keratinocyte cell lines overexpressing NM23-Hl and/or-H2. Whereas the enhanced levels of NM23 did not affect cell proliferation in monoculture, NM23-H2 and double transfectants but not NM23-Hl transfectants formed a strongly hyperthickened epithelium in three-dimensional organotypic cultures. The abnormal epithelial morphology resulted from enhanced proliferation, reduced apoptosis and alterations in the differentiation pattern. These findings suggest that epidermal homeostasis depends on a tight regulation of the levels of NM23 isoforms
    Type of Publication: Journal article published
    PubMed ID: 16862176
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