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  • 1
    Keywords: RECEPTOR ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; proliferation ; Germany ; IN-VIVO ; NETWORKS ; SYSTEM ; GENE ; GENE-EXPRESSION ; HYBRIDIZATION ; transcription ; DIFFERENTIATION ; TISSUE ; COMPLEX ; COMPLEXES ; TRANSCRIPTION FACTOR ; AP-1 ; KERATINOCYTES ; SKIN ; C-JUN ; fibroblasts ; cytokines ; antibodies ; antibody ; MOUSE ; IN-SITU ; gene expression ; REPAIR ; SIGNALING PATHWAY ; HUMAN KERATINOCYTES ; Jun ; gene expression profiling ; expression profiling ; COLONY-STIMULATING FACTOR ; FACTOR GENE-EXPRESSION ; FUNCTIONAL EXPRESSION ; in situ hybridization ; keratinocyte ; regulation ; mesenchyme ; SDF-1 ; CHEMOKINE RECEPTORS ; INFLAMMATORY CYTOKINES ; CELL-DERIVED FACTOR ; CXCL12 ; GROWTH-ASSOCIATED MOLECULE ; HB-GAM ; LARGE INDUCTION ; pleiotrophin
    Abstract: In skin, fibroblasts of the connective tissue play a decisive role in epidermal homeostasis and repair by contributing to the regulation of keratinocyte proliferation and differentiation. The AP-1 transcription factor subunit JUN plays a crucial role in this mesenchymal-epithelial interplay by regulating the expression of two critical paracrine-acting cytokines, keratinocyte growth factor (KGF) and granulocyte-macrophage colony-stimulating factor (GMCSF). We have performed gene expression profiling of wildtype and Jun(-/-) mouse embryonic fibroblasts to identify additional players involved in this complex network, and have found pleiotrophin (PTN) and the stromal cell-derived factor 1 (SDF-1) as novel JUN-regulated factors. Both cytokines are expressed by dermal fibroblasts in vivo, as shown by semi-quantitative RT-PCR and in situ hybridization on murine skin sections. Using a heterologous feeder layer co-culture system, we demonstrated that PTN and SDF-1 exert a mitogenic effect on primary human keratinocytes. Moreover, SDF-1-induced keratinocyte proliferation could be specifically inhibited by neutralizing antibodies against SDF-1 or its receptor, CXCR4. Consistent with its role in promoting keratinocyte growth, PTN was upregulated during cutaneous wound healing in vivo. Interestingly, co-cultivation with keratinocytes stimulated PTN expression but repressed SDF-1 production in fibroblasts, demonstrating the complexity of the paracrine regulatory cytokine networks that control skin homeostasis and regeneration
    Type of Publication: Journal article published
    PubMed ID: 15840658
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  • 2
    Keywords: EXPRESSION ; GENE ; PROTEIN ; DIFFERENTIATION ; METASTASIS ; DISSEMINATED TUMOR-CELLS ; micrometastasis ; MAMMARY-GLAND ; SELF-RENEWAL ; CTBP
    Abstract: Regulatory pathways that drive early hematogenous dissemination of tumor cells are insufficiently defined. Here, we used the presence of disseminated tumor cells (DTC) in the bone marrow to define patients with early disseminated breast cancer and identified low retinoic acid-induced 2 (RAI2) expression to be significantly associated with DTC status. Low RAI2 expression was also shown to be an independent poor prognostic factor in 10 different cancer datasets. Depletion of RAI2 protein in luminal breast cancer cell lines resulted in dedifferentiation marked by downregulation of ERalpha, FOXA1, and GATA3, together with increased invasiveness and activation of AKT signaling. Functional analysis of the previously uncharacterized RAI2 protein revealed molecular interaction with CtBP transcriptional regulators and an overlapping function in controlling the expression of a number of key target genes involved in breast cancer. These results suggest that RAI2 is a new metastasis-associated protein that sustains differentiation of luminal breast epithelial cells. SIGNIFICANCE: We identified downregulation of RAI2 as a novel metastasis-associated genetic alteration especially associated with early occurring bone metastasis in ERalpha-positive breast tumors. We specified the role of the RAI2 protein to function as a transcriptional regulator that controls the expression of several key regulators of breast epithelial integrity and cancer. Cancer Discov; 5(5); 506-19. (c)2015 AACR. See related commentary by Esposito and Kang, p. 466 This article is highlighted in the In This Issue feature, p. 453.
    Type of Publication: Journal article published
    PubMed ID: 25716347
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  • 3
    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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  • 4
    Keywords: EXPRESSION ; GROWTH ; IN-VITRO ; evaluation ; Germany ; IN-VIVO ; VIVO ; CDNA ; CLONES ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; transcription ; TISSUE ; RELEASE ; NF-KAPPA-B ; INJURIES ; MECHANISM ; TRANSCRIPTION FACTOR ; AP-1 ; KERATINOCYTES ; mechanisms ; SKIN ; C-JUN ; fibroblasts ; SIGNAL ; TARGET ; IDENTIFICATION ; gene expression ; SUBUNIT ; REPAIR ; WILD-TYPE ; Jun ; SUBUNITS ; GROWTH-FACTOR-BETA ; DIFFERENTIAL EXPRESSION ; expression profiling ; DISSECTION ; SECTIONS ; INJURY ; CDNA MICROARRAY ; MOLECULAR-MECHANISM ; fibroblast ; mesenchyme ; GLUCOCORTICOID-TREATED MICE ; MOUSE DEVELOPMENT ; SKIN FRAGILITY
    Abstract: Mesenchymal - epithelial interactions are increasingly considered to be of vital importance for epithelial homeostasis and regeneration. In skin, the transcription factor AP-1 was shown to be critically involved in the communication between keratinocytes and dermal. broblasts. After skin injury, the release of IL-1 from keratinocytes induces the activity of the AP-1 subunits c-Jun and JunB in. broblasts leading to a global change in gene expression. To identify AP-1 target genes in. broblasts, which are involved in the process of cutaneous repair, we performed gene expression pro. ling of wild-type, c-jun- and junB-deficient. broblasts in response to IL-1, mimicking the initial phase of wound healing. Using a 15K cDNA collection, over 1000 genes were found to be Jun-dependent and additional 300 clones showed IL-1 responsiveness. Combinatorial evaluation allowed for the dissection of the specific contribution of either AP-1 subunit to gene regulation. Besides previously identified genes that are involved in cutaneous repair, we have identified novel genes regulated during wound healing in vivo and showed their expression by. broblasts on wound sections. The identification of novel Jun target genes should provide a basis for understanding the molecular mechanisms underlying mesenchymal - epithelial interactions and the critical contribution of AP-1 to tissue homeostasis and repair
    Type of Publication: Journal article published
    PubMed ID: 15273721
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  • 5
    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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