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  • CARCINOGENESIS  (9)
  • AP-1  (8)
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  • 1
    Keywords: CELL ; Germany ; APOPTOSIS ; CELLS ; GROWTH ; PATHWAY ; PATHWAYS ; AP-1 ; ACTIVATION ; TIME ; MICE ; EFFICIENCY ; TOOL ; NEW-YORK ; INDUCTION ; T cells ; T-CELL ; T-CELLS ; T cell ; treatment ; SIGNAL ; c-Fos ; EAST ; c-Fos,apoptosis,early activation,induction,T cells ; GENOTYPES ; SIGNALING PATHWAY ; STIMULI ; WILD-TYPE ; SIGNALING PATHWAYS
    Abstract: We used c-Fos-deficient activated T cells from the spleen and c-Fos-deficient thymocytes to address the capacity of these cells to undergo apoptosis in response to various stimuli. To determine the role of c-Fos in apoptosis regulation in thymocytes, we challenged thymocytes from wild-type and c-Fos-deficient mice with either TPA or the glucocorticoid dexamethasone. After various time points cells were stained according to the Nicoletti method and analyzed by FACS. Thymocytes from both genotypes exhibited similar efficiency of apoptosis in response to treatment with TPA or dexamethasone. Our data provide clear evidence that c-Fos is not required for apoptosis regulation in activated T cells as well as in thymocytes
    Type of Publication: Book chapter
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  • 2
    Keywords: CELLS ; EXPRESSION ; GROWTH ; tumor ; IN-VIVO ; KINASE ; PATHWAYS ; GENE ; GENES ; PROTEIN ; MICE ; CARCINOGENESIS ; KERATINOCYTES ; SKIN ; PROTEIN-KINASE ; MAP KINASE ; LESIONS ; resistance ; INDUCED APOPTOSIS ; NUMBER ; epidermis ; GROWTH ARREST ; signaling ; RE ; TUMOR-SUPPRESSOR ; TUMORIGENESIS ; SIZE ; ERK ; function ; INVASIVENESS
    Abstract: Extracellular signal-regulated kinases (ERK) regulate cellular functions in response to a variety of external signals. However, the specific functions of individual ERK isoforms are largely unknown. Hence, we have investigated the specific function of ERK1 in skin homeostasis and tumorigenesis in ERK1 knockout mice. They spontaneously develop cutaneous lesions and hyperkeratosis with epidermis thickness. Skin hyperproliferation and inflammation induced by application of 12-O-tetradecanoylphorbol-13-acetate (TPA) is strongly reduced in mutant mice. ERKI-/- mice are resistant to development of skin papillomas induced by 7,12-dimethylbenz(a)anthracene (DMBA) and promoted by TPA. Tumor appearance was delayed, their formation was less frequent, and their number and size were reduced. Keratinocytes obtained from knockout mice showed reduced growth and resistance to apoptotic signals, accompanied by an impaired expression of genes implicated in growth control and invasiveness. These results highlight the importance of ERK1 in skin homeostasis and in the process of skin tumor development
    Type of Publication: Journal article published
    PubMed ID: 16510590
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  • 3
    Keywords: RECEPTOR ; CANCER ; IN-VITRO ; DIFFERENTIATION ; FAMILY ; CARCINOGENESIS ; HUMAN-PAPILLOMAVIRUS ; HEAD ; inflammation ; DEPENDENT PATHWAY
    Abstract: S100/calgranulins (S100A8, S100A9 and S100A12) are key players of innate immune function and elevated levels are a characteristic feature of acute and chronic inflammation, and inflammation-associated carcinogenesis. However, reduced S100A8 and S100A9 expression has been detected for squamous cell carcinoma, including the head and neck region (HNSCC), which originate from mucosal epithelia with abundant expression of both proteins under physiological conditions. In contrast to S100A8 and S100A9, only sparse information is available for S100A12 and a comparative study of all three S100/calgranulins in HNSCC is still missing. We analyzed S100/calgranulin protein levels in a retrospective patient cohort (n=131) of oropharyngeal squamous cell carcinoma (OPSCC) by immunohistochemical staining of tissue microarrays. Common characteristics of all three S100/calgranulins were: (i) abundant expression in supra-basal keratinocytes of normal mucosa with predominant nuclear staining, (ii) low expression in 30.4-51.9% of primary OPSCCs and (iii) variable accumulation of S100/calgranulin-positive immune cells in the tumor stroma. These features were associated with histopathological characteristics, such as tumor grade, lymph node metastasis and tumor stage. Furthermore, univariate and multivariate analysis revealed worse overall survival of OPSCC patients with simultaneous reduction of S100A8 and S100A12 expression, while expression of S100A9 or presence of the S100A8/S100A9 heterodimer had no impact, suggesting distinct regulation and function of individual S100/calgranulins in the pathogenesis of HNSCCs. What's new? Inflammation can alter the expression of specific proteins, and in the context of head and neck squamous cell carcinoma (HNSCC), which involves a high degree of inflammation, those changes may be of diagnostic or prognostic significance. Here, reduced expression of calcium-binding S100/calgranulin proteins was found to be a common feature of oropharyngeal SCC. Moreover, simultaneous low protein expression of S100A8 and S100A12 in tumor cells was an independent risk factor for unfavorable overall survival. The regulation and function of S100/calgranulins likely is context-dependent, with differences between mucosal and squamous epithelia.
    Type of Publication: Journal article published
    PubMed ID: 25302747
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  • 4
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; Germany ; human ; SYSTEM ; DEATH ; SITE ; GENE ; GENE-EXPRESSION ; DRUG ; TISSUE ; NF-KAPPA-B ; LIGAND ; AP-1 ; primary ; INDUCTION ; T cells ; T-CELLS ; BINDING ; C-JUN ; SEQUENCE ; TRANSCRIPTION FACTORS ; ASSAY ; activation-induced cell death ; c-Fos ; CARCINOMA CELLS ; CD95 ligand ; CELL-DEATH ; CYCLOSPORINE-A ; FAS-LIGAND EXPRESSION ; INDUCED APOPTOSIS ; MOBILITY ; PROMOTER ; UP-REGULATION
    Abstract: The CD95 (APO-1/Fas) system plays a major role in induction of apoptosis in lymphoid and nonlymphoid tissues. The CD95 (APO- 1/Fas) ligand (CD95L) is induced in response to a variety of signals including TCR/CD3 stimulation or application of chemotherapeutic drugs. Here we report that an AP-1 site located in the 5' untranslated region of the CD95L gene is required for TCR/CD3-mediated induction of the human CD95L promoter. Electrophoretic mobility shift assays using nuclear extracts of Jurkat T cells as well as TCR/CD3-restimulated primary human T cells demonstrated specific binding of AP-1, predominantly composed of c-Jun and FosB, to this sequence. Ectopic expression of transdominant negative Jun mutants strongly reduced CD95L promoter activity and activation-induced cell death (AICD), confirming the functional significance of FosB/c-Jun binding. Thus, our results demonstrate an important novel function for FosB dimerized with c-Jun in TCR/CD3- mediated AICD in human T cells
    Type of Publication: Journal article published
    PubMed ID: 12618758
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  • 5
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; carcinoma ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; PROTEIN ; SAMPLE ; SAMPLES ; murine ; AP-1 ; CARCINOGENESIS ; tumour ; SKIN ; MOUSE ; TRANSCRIPTION FACTORS ; IDENTIFICATION ; PROGRESSION ; gene expression ; PROMOTERS ; skin carcinogenesis ; METASTASIS ; SSH ; PCR ; TRANSFORMATION ; EPITHELIAL-CELLS ; squamous cell carcinoma ; FRAGMENTS ; MULTISTAGE CARCINOGENESIS ; real-time PCR ; expression profiling ; PHORBOL ESTER ; CDNA MICROARRAY ; NMRI MOUSE SKIN ; tumour promoter
    Abstract: Malignant transformation of mouse skin by chemical carcinogens and tumour promoters, such as the phorbol ester 12-O- tetradecanoylphorbol-13-acetate (TPA), is a multi-stage process that leads to squamous cell carcinoma (SCC) formation. In an effort to identify turnour-associated genes, we studied the influence of short-term TPA-treatment on the gene expression profile of murine skin. A comprehensive microarray with some 5,000 murine gene specific cDNA fragments was established and hybridised with pooled RNA derived from control and TPA-treated dorsal skin samples. Of these genes, 54 were up- and 35 were down-regulated upon TPA application. Additionally, we performed suppression subtractive hybridisation (SSH) with respective RNA pools to generate and analyse a cDNA library enriched for TPA- inducible genes. Expression data of selected genes were confirmed by quantitative real-time PCR and Northern blot analysis. Comparison of microarray and SSH data revealed that 26% of up-regulated genes identified by expression profiling matched with those present in the SSH library. Besides numerous known genes, we identified a large set of unknown cDNAs that represent previously unrecognised TPA-regulated genes in murine skin with potential function in tumour promotion. Additionally, some TPA-induced genes, such as SprrIA, Saa3, junB, II4ralpha, Gp38, RalGDS and Slpi exhibit high basal level in advanced stages of skin carcinogenesis, suggesting that at least a subgroup of the identified TPA-regulated genes may contribute to tumour progression and metastasis. (C) 2003 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 12640676
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  • 6
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; SURVIVAL ; carcinoma ; CELL ; Germany ; human ; MODEL ; PATHWAY ; PATHWAYS ; NETWORK ; SUPPORT ; DEATH ; HEPATOCELLULAR-CARCINOMA ; liver ; GENE ; GENES ; PROTEIN ; PROTEINS ; TISSUE ; NF-KAPPA-B ; ACTIVATION ; murine ; CARCINOGENESIS ; INDUCTION ; SIGNAL ; TARGET ; MOUSE ; hepatocarcinogenesis ; hepatocellular carcinoma ; PROGRESSION ; CELL-DEATH ; CELL-LINE ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; RAGE ; MOUSE MODEL ; KAPPA-B ; OXIDATIVE STRESS ; expression profiling ; inflammation ; signaling ; MOLECULAR-MECHANISMS ; cell death ; CANCER PROGRESSION ; USA ; GROWTH-CONTROL ; SUPPRESSOR-CELLS ; nuclear factor kappa B ; COEXPRESSION ; COMPENSATORY PROLIFERATION
    Abstract: The nuclear factor-kappaB (NF-kappa B) signaling pathway has been recently shown to participate in inflammation-induced cancer progression. Here, we describe a detailed analysis of the NF-kappa B-dependent gene regulatory network in the well-established Mdr2 knockout mouse model of inflammation-associated liver carcinogenesis. Expression profiling of NF-kappa B-deficient and NF-kappa B-proficient hepatocellular carcinoma (HCC) revealed a comprehensive list of known and novel putative NF-kappa B target genes, including S100a8 and S100a9. We detected increased co-expression of S100A8 and S100A9 proteins in mouse HCC cells, in human HCC tissue, and in the HCC cell line Hep3B on ectopic RelA expression. Finally, we found a synergistic function for S100A8 and S100A9 in Hep3B cells resulting in a significant induction of reactive oxygen species (ROS), accompanied by enhanced cell survival. Conclusion: We identified S100A8 and S100A9 as novel NF-kappa B target genes in HCC cells during inflammation-associated liver carcinogenesis and provide experimental evidence that increased co-expression of both proteins supports malignant progression by activation of ROS-dependent signaling pathways and protection from cell death. (HEPATOLOGY 2009;50: 1251-1262.)
    Type of Publication: Journal article published
    PubMed ID: 19670424
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  • 7
    Keywords: ENDOTHELIAL-CELLS ; PROTEINS ; CARCINOGENESIS ; mechanisms ; NECROSIS-FACTOR-ALPHA ; PATHOGENESIS ; GLYCATION END-PRODUCTS ; KAPPA-B ; epidermis ; HAIR FOLLICLE
    Abstract: The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor causally related to the pathogenesis of acute and chronic inflammation. In a mouse model of inflammation-driven skin carcinogenesis, RAGE deletion conferred protection from the development of skin tumors due to a severely impaired cutaneous inflammation. Although the impact of RAGE expression in immune cells was shown to be essential for the maintenance of a cutaneous inflammatory reaction, the role of RAGE in keratinocytes remained unsolved. Using mice harboring a keratinocyte-specific deletion of RAGE, we analyzed its role in the regulation of an acute inflammatory response that was induced by topical treatment of the back skin with the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA). We show that RAGE expression in cutaneous keratinocytes modulates the strength and kinetics of acute inflammation and supports the maintenance of epidermal keratinocyte activation. To address the underlying molecular mechanism, we isolated interfollicular epidermis by laser microdissection for gene expression analysis, and identified RAGE as a regulator in the temporal control of TPA-induced epidermal tumor necrosis factor alpha transcript levels. In summary, our data demonstrate that RAGE expression in keratinocytes is critically involved in the perpetuation of acute inflammation and support the central role of RAGE in paracrine communication between keratinocytes and stromal immune cells.
    Type of Publication: Journal article published
    PubMed ID: 23594597
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  • 8
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; INHIBITOR ; tumor ; carcinoma ; Germany ; IN-VIVO ; VITRO ; GENE ; PROTEIN ; TUMORS ; MICE ; PATIENT ; FAMILY ; AP-1 ; CARCINOGENESIS ; INDUCTION ; KERATINOCYTES ; SKIN ; BINDING ; fibroblasts ; MOUSE ; c-Fos ; PROMOTER ; MOUSE SKIN ; TRANSFORMATION ; BENIGN ; CARCINOMAS ; squamous cell carcinoma ; GLUCOCORTICOID-RECEPTOR ; SKIN-CANCER ; BINDING PROTEIN ; keratinocyte ; TRANSITION ; MALIGNANT PROGRESSION ; INTERSTITIAL COLLAGENASE ; CELL-CARCINOMA ; dexamethasone ; MOUSE KERATINOCYTES ; RECYCLING ENDOSOMES
    Abstract: Malignant transformation of mouse skin by tumor promoters and chemical carcinogens, such as the phorhol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), is a multistage process leading to the formation of squamous cell carcinomas. it has been shown that mice lacking the AP-1 family member c-Fos exhibit an impaired transition from benign to malignant skin tumors. Here, we demonstrate enhanced expression of the small Ras-related GTPase Rab11a after short-term TPA treatment of mouse back skin. Expression of Rab11a in vivo and in vitro critically depended on c-Fos, because TPA application to the back skin of c-Fos-deficient mice and to mouse embryonic fibroblasts did not induce Rab11a mRNA or protein expression. Moreover, dexamethasone, which is a potent inhibitor of AP-1-mediated transactivation that exhibits anti-inflammatory and antitumor promoting activities, inhibited TPA-induced expression of Rab11a. Within the Rab11a gene promoter, we identified a functional AP-1 binding element that exhibited elevated c-Fos binding activity after TPA treatment of keratinocytes. Enhanced expression was not restricted to chemically induced mouse skin tumors but was also found in tumor specimens derived from patients with epithelial skin tumors. These data identify Rab11a as a novel, tumor-associated c-Fos/AP-1 target and may point to an as yet unrecognized function of Rab11a in the development of skin cancer
    Type of Publication: Journal article published
    PubMed ID: 15972968
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  • 9
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; CELL ; Germany ; human ; IN-VIVO ; KINASE ; MODEL ; VIVO ; GENE ; GENE-EXPRESSION ; GENES ; HYBRIDIZATION ; PROTEIN ; RNA ; METABOLISM ; cell line ; LINES ; MICE ; DNA ; CARCINOGENESIS ; animals ; KERATINOCYTES ; SKIN ; BIOLOGY ; cell cycle ; CELL-CYCLE ; CELL-LINES ; CYCLE ; DOWN-REGULATION ; MOUSE ; IDENTIFICATION ; IN-SITU ; PROGRESSION ; MALIGNANCIES ; gene expression ; EXPRESSION ANALYSIS ; HUMANS ; DESIGN ; UP-REGULATION ; MOUSE SKIN ; skin carcinogenesis ; genetics ; statistics ; CELL-LINE ; LINE ; ADHESION ; CELL-ADHESION ; ONCOGENE ; INVOLVEMENT ; RT-PCR ; KINETICS ; cell lines ; heredity ; SKIN-CANCER ; HUMAN SKIN ; in situ hybridization ; MALIGNANCY ; ONCOLOGY ; ANNOTATION ; ENHANCED EXPRESSION ; cell adhesion ; LEVEL ; analysis ; CANCER DEVELOPMENT ; cluster analysis ; S100A8 ; MAP ; in vivo ; RELEVANCE ; Oligonucleotide Array Sequence Analysis ; SPECIMENS ; animal ; Carcinoma,Squamous Cell ; SQUAMOUS-CELL ; SET ; animal model ; molecular genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Skin Neoplasms ; Cell Line,Tumor ; cytology ; DNA,Complementary ; epithelial skin cancer ; Gene Expression Regulation,Neoplastic ; HUMAN-SKIN ; Microscopy,Fluorescence ; Protein-Serine-Threonine Kinases ; RNA,Messenger ; tumour specimen
    Abstract: Chemically induced mouse skin carcinogenesis represents the most extensively utilized animal model to unravel the multistage nature of tumour development and to design novel therapeutic concepts of human epithelial neoplasia. We combined this tumour model with comprehensive gene expression analysis and could identify a large set of novel tumour-associated genes that have not been associated with epithelial skin cancer development yet. Expression data of selected genes were confirmed by semiquantitative and quantitative RT-PCR as well as in situ hybridization and immunofluorescence analysis on mouse tumour sections. Enhanced expression of genes identified in our screen was also demonstrated in mouse keratinocyte cell lines that form tumours in vivo. Self-organizing map clustering was performed to identify different kinetics of gene expression and coregulation during skin cancer progression. Detailed analysis of differential expressed genes according to their functional annotation confirmed the involvement of several biological processes, such as regulation of cell cycle, apoptosis, extracellular proteolysis and cell adhesion, during skin malignancy. Finally, we detected high transcript levels of ANXA1, LCN2 and S100A8 as well as reduced levels for NDR2 protein in human skin tumour specimens demonstrating that tumour-associated genes identified in the chemically induced tumour model might be of great relevance for the understanding of human epithelial malignancies as well
    Type of Publication: Journal article published
    PubMed ID: 16247483
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  • 10
    Keywords: CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; proliferation ; CELL ; Germany ; VITRO ; transcription ; TISSUE ; LINES ; MICE ; FAMILY ; TRANSCRIPTION FACTOR ; AP-1 ; TISSUES ; cell cycle ; CELL-CYCLE ; CYCLE ; MEMBER ; SIGNAL ; bone marrow ; BONE-MARROW ; TRANSGENIC MICE ; c-Fos ; NUMBER ; transgenic ; LINE ; MUTANT MICE ; ACTIVATING TRANSCRIPTION FACTOR-2 ; AP-1,bone,chondrocytes,cell cycle,osteoblasts,osteoporosis ; BONE-FORMATION ; EMBRYONIC LETHALITY ; GROWTH-PLATE CHONDROCYTES ; HERITABLE DISEASES ; LINEAGE DETERMINATION ; MOLECULAR INSIGHTS ; NATRIURETIC PEPTIDE ; OSTEOBLAST-LIKE CELLS ; OSTEOPOROSIS ; REGULATOR ; REGULATORS ; SKELETAL DEVELOPMENT
    Abstract: Functional analysis in mice has established an absolute requirement of JunB, a member of the AP-1 transcription factor family, during early embryonic development. To investigate the role of JunB during mid and late gestation and postnatally Ubi-junB transgenic mice were used to generate two junB(-/-) Ubi-junB mutant lines, in which embryonic lethality was rescued but strongly reduced JunB; expression in several adult tissues was observed. Mutant mice from both rescue lines were growth retarded and shared significantly reduced longitudinal bone growth. Mutant long bones were characterised by reduced numbers of growth plate chondrocytes and a severe osteoporosis. Decreased JunB levels in epiphysal growth plate chondrocytes and bone lining osteoblasts correlated with deregulated expression of Cyclin A, Cyclin D1 and p16(INK4a), key regulators of cell cycle control. Furthermore, junB(-/-) Ubi-junB bone marrow stromal cells were unable to differentiate into bone forming osteoblasts in vitro. Our data demonstrate that JunB plays a crucial role in endochondral ossification by regulating proliferation and function of chondrocytes and osteoblasts
    Type of Publication: Journal article published
    PubMed ID: 14576352
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