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  • 1
    Keywords: ANGIOGENESIS ; EXPRESSION ; GROWTH ; SURVIVAL ; CELL ; ENDOTHELIAL GROWTH-FACTOR ; human ; IN-VIVO ; VIVO ; SUPPORT ; DEATH ; GENE ; COMPONENTS ; MOLECULES ; MICE ; recombination ; MOLECULE ; knockout ; MOUSE ; CELL-DEATH ; AGE ; MUTATION ; COMPONENT ; inactivation ; EXTRACELLULAR-MATRIX ; PHENOTYPE ; DEGRADATION ; RECRUITMENT ; BONE-FORMATION ; SKELETAL DEVELOPMENT ; HOMOLOGOUS RECOMBINATION ; LACKING ; MMP ; MATRIX ; DEFICIENCY ; PROGRAM ; VARIANT ; collagen ; MICE LACKING ; II COLLAGEN ; aggrecan ; chondrocyte ; collagenase ; COLLAGENASE CLEAVAGE SITE ; DEVELOPING LONG BONES ; hypertrophic cartilage ; HYPERTROPHIC CHONDROCYTES ; OSTEOARTHRITIC CARTILAGE ; PARATHYROID-HORMONE ; SPONDYLOEPIMETAPHYSEAL DYSPLASIA ; trabecular bone
    Abstract: The assembly and degradation of extracellular matrix (ECM) molecules are crucial processes during bone development. In this study, we show that ECM remodeling is a critical rate-limiting step in endochondral bone formation. Matrix metalloproteinase (MMP) 13 (collagenase 3) is poised to play a crucial role in bone formation and remodeling because of its expression both in terminal hypertrophic chondrocytes in the growth plate. p and in osteoblasts. Moreover, a mutation in the human MMP13 gene causes the Missouri variant of spondyloepimetaphyseal dysplasia. Inactivation of Mmp13 in mice through homologous recombination led to abnormal skeletal growth plate development. Chondrocytes differentiated normally but their exit from the growth plate was delayed. The severity of the Mmp13-null growth plate phenotype increased until about 5 weeks and completely resolved by 12 weeks of age. Mmp13-null mice had increased trabecular bone, which persisted for months. Conditional inactivation of Mmp13 in chondrocytes and osteoblasts showed that increases in trabecular bone occur independently of the improper cartilage ECM degradation caused by Mmp13 deficiency in late hypertrophic chondrocytes. Our studies identified the two major components of the cartilage ECM, collagen type II and aggrecan, as in vivo substrates for MMP13. We found that degradation of cartilage collagen and aggrecan is a coordinated process in which MMP13 works synergistically with MMP9. Mice lacking both MMP13 and MMP9 had severely impaired endochondral bone, characterized by diminished ECM remodeling, prolonged chondrocyte survival, delayed vascular recruitment and defective trabecular bone formation (resulting in drastically shortened bones). These data support the hypothesis that proper ECM remodeling is the dominant rate-limiting process for programmed cell death, angiogenesis and osteoblast recruitment during normal skeletal morphogenesis
    Type of Publication: Journal article published
    PubMed ID: 15539485
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  • 2
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; INHIBITOR ; tumor ; TUMOR-CELLS ; CELL ; Germany ; IN-VIVO ; INHIBITION ; LUNG ; lung cancer ; LUNG-CANCER ; DEATH ; GENE ; PROTEIN ; RNA ; DRUG ; TISSUE ; LINES ; MARKER ; PROTEIN FAMILY ; CELL-LINES ; TARGET ; ASSAY ; resistance ; NUMBER ; CELL-LINE ; LINE ; CANCER-CELLS ; MAMMALIAN-CELLS ; RT-PCR ; IAP PROTEINS ; cell lines ; TUMOR CELLS ; ETOPOSIDE ; non-small cell lung cancer ; INTERFERENCE ; RNA INTERFERENCE ; TUMOR-CELL ; ASSAYS ; COLONY FORMATION ; RNAi ; NSCLC ; Livin ; ML-IAP ; inhibitor of apoptosis ; SURVIVIN MESSENGER-RNA
    Abstract: Cancer cells are typically characterized by increased resistance towards apoptosis. Livin (alternatively called ML-IAP or KIAP) is an anti-apoptotic protein which is expressed in several cancer forms. Using real-time reverse transcription-polymerase chain reaction (RT-PCR), we confirmed livin expression in a significant portion of non-small cell lung cancer (NSCLC) tissue samples and,, in addition, detected livin expression in a number of NSCLC cell lines. In order to elucidate whether livin contributes to the apoptotic resistance of lung cancer cells, we silenced endogenous livin expression in a panel of cancer-derived NSCLC cell tines by RNA interference (RNAi). We observed that the targeted inhibition of livin strongly sensitized NSCLC cells to different pro-apoptotic stimuli, such as UV-irradiation or the chemotherapeutic drug etoposide. In addition, long-term silencing of livin blocked the outgrowth of NSCLC cells in colony formation assays. These effects of small interfering (si)RNA were specific for livin-expressing tumor cells. Our results indicate that Livin is an important contributor to the apoptosis resistance of NSCLC cells and may serve as a novel molecular target for therapeutic inhibition in NSCLC. (C) 2006 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16965834
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  • 3
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; PROTEINS ; transcription ; TISSUE ; TUMORS ; MICE ; ACTIVATION ; COMPLEX ; LIGAND ; RESPONSES ; COMPLEXES ; CUTTING EDGE ; IFN-GAMMA ; MACROPHAGES ; TRANSCRIPTION FACTOR ; AP-1 ; TISSUES ; SKIN ; TARGET ; STRESS ; STRESS-RESPONSE ; LIGANDS ; NATURAL-KILLER-CELLS ; NK cells ; CD8(+) ; IMMUNE-RESPONSE ; CELL-SURFACE ; RE ; TUMORIGENESIS ; RHEUMATOID-ARTHRITIS ; LEVEL ; MICE LACKING JUNB ; immunology ; TRANSCRIPTION FACTOR AP-1 ; NKG2D RECEPTOR
    Abstract: The activating receptor NKG2D and its ligands RAE-1 play an important role in the NK, gamma delta(+), and CD8(+) T cell-mediated immune response to tumors. Expression levels of RAE-1 on target cells have to be tightly controlled to allow immune cell activation against tumors but to avoid destruction of healthy tissues. In this study, we report that cell surface expression of RAE-1 epsilon is greatly enhanced on cells lacking JunB, a subunit of the transcription complex AP-1. Furthermore, tissue-specific junB knockout mice respond to 12-O-tetradecanoyl-phorbol-13-acetate, a potent AP-1 activator, with markedly increased and sustained epidermal RAE-1 epsilon expression. Accordingly, junB-deficient cells are efficiently killed via NKG2D by NK cells and induce IFN-gamma production. Our data indicate that the transcription factor AP-1, which is involved in tumorigenesis and cellular stress responses, regulates RAE-1 epsilon. Thus, up-regulated RAE-1 epsilon expression due to low levels of JunB could alert immune cells to tumors and stressed cells
    Type of Publication: Journal article published
    PubMed ID: 16365389
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  • 4
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; GROWTH ; proliferation ; carcinoma ; CELL ; CELL-PROLIFERATION ; Germany ; LUNG ; DIAGNOSIS ; lung cancer ; LUNG-CANCER ; DEATH ; GENE ; GENES ; microarray ; PROTEIN ; cell line ; meningioma ; TISSUE ; LINES ; primary ; DOMAIN ; tumour ; SKIN ; BIOLOGY ; CELL-LINES ; MEMBER ; MOLECULAR-BIOLOGY ; SIGNAL ; PROGRESSION ; ASSAY ; INDUCED APOPTOSIS ; genetics ; COUNTRIES ; skin cancer ; CELL-LINE ; LINE ; ONCOGENE ; SUPERFAMILY ; EPITHELIAL-CELLS ; Jun ; PHENOTYPE ; STRATEGIES ; OVEREXPRESSION ; cell lines ; heredity ; LUNG-CARCINOMA ; SKIN-CANCER ; tumour suppressor gene ; ORIGIN ; molecular biology ; molecular ; ONCOLOGY ; non-small cell lung carcinoma ; SUPPRESSOR GENE ; cell proliferation ; SUPPRESSOR ; tumour suppressor ; NSCLC ; SET ; BREAST-CANCER CELLS ; DAL-1 ; ferm containing 3 ; GROWTH SUPPRESSION ; protein 4.1 ; PROTEIN 4.1B
    Abstract: Lung cancer including non-small cell lung carcinoma (NSCLC) represents a leading cause of cancer death in Western countries. Yet, understanding its pathobiology to improve early diagnosis and therapeutic strategies is still a major challenge of today's biomedical research. We analyzed a set of differentially regulated genes that were identifi. ed in skin cancer by a comprehensive microarray study, for their expression in NSCLC. We found that ferm domain containing protein 3 (FRMD3), a member of the protein 4.1 superfamily, is expressed in normal lung tissue but silenced in 54 out of 58 independent primary NSCLC tumours compared to patient-matched normal lung tissue. FRMD3 overexpression in different epithelial cell lines resulted in a decreased clonogenicity as measured by colony formation assay. Although cell attachment capabilities and cell proliferation rate remained unchanged, this phenotype was most likely owing to induced apoptosis. Our data identify FRMD3 as a novel putative tumour suppressor gene suggesting an important role in the origin and progression of lung cancer
    Type of Publication: Journal article published
    PubMed ID: 17260017
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  • 5
    Keywords: ANGIOGENESIS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; INVASION ; carcinoma ; CELL ; Germany ; VITRO ; PROTEIN ; RNA ; MICE ; ACTIVATION ; CARCINOGENESIS ; CONTRAST ; SKIN ; fibroblasts ; ASSOCIATION ; BREAST-CANCER ; cytokines ; PROGRESSION ; TUMOR PROGRESSION ; POOR-PROGNOSIS ; VEGF ; CYTOKINE ; CELL CARCINOMA ; ONCOLOGY ; fibroblast ; MATRIX METALLOPROTEINASES ; endothelial cells ; ONSET ; SQUAMOUS-CELL ; matrix metalloproteinase ; METALLOPROTEINASE 13-DEFICIENT MICE ; MAINTENANCE ; stroma ; AREA ; PROMOTE ; MMP13 ; COLLAGENASE-3 EXPRESSION ; MMP-13
    Abstract: Matrix metalloproteinases (MMPs) such as MMP13 promote tumour growth and progression by mediating extracellular matrix (ECM) reorganization and regulating the biological activity of cytokines. Using Mmp13-/- mice, we demonstrate an essential role of this single collagenase for highly malignant and invasive growth in skin squamous cell carcinoma (SCC). Lack of host MMP13 strongly impaired tumour growth of malignant SCC cells, leading to small, mostly avascular cysts. While initial stromal activation in tumour transplants of Mmp13+/+ and Mmp13-/- animals was similar, MMP13 was essential for maintenance of angiogenesis and for invasion. MMP13 was induced in fibroblasts of the wild-type animals at the onset of invasion and correlated with a strong increase in vascular endothelial growth factor (VEGF) protein and its association with vascular endothelial growth factor receptor-2 on endothelial cells in invasive areas. In contrast, VEGF protein in the stroma was barely detectable and tumour invasion was downregulated in Mmp13-/- animals, despite ongoing VEGF messenger RNA expression. Taken together with in vitro data showing the release of VEGF from the ECM by MMP13 expressing fibroblasts, these data strongly suggest a crucial role of MMP13 in promoting angiogenesis via releasing VEGF from the ECM and thus allowing the invasive growth of the SCC cells
    Type of Publication: Journal article published
    PubMed ID: 19892798
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  • 6
    Keywords: MICE ; animals ; HUMANS ; PHENOTYPE ; HYPERPLASIA ; female ; Aspartic Acid Endopeptidases/*genetics/metabolism ; Carcinogens/toxicity ; Cell Differentiation/physiology ; Cell Division/physiology ; Gene Expression/physiology ; Keratinocytes/pathology/physiology ; Lac Operon ; Mice, Inbred C57BL ; Mice, Transgenic ; Promoter Regions, Genetic/physiology ; Regeneration/*physiology ; Skin/drug effects/*injuries/*pathology ; Tetradecanoylphorbol Acetate/toxicity ; Ubiquitin C/genetics ; Wound Healing/*physiology
    Abstract: Recently, we identified an AP-1-dependent target gene in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated mouse back skin, which encodes a retroviral-like aspartic proteinase (Taps/Asprv1). Taps expression was detected almost exclusively in stratified epithelia of mouse embryos and adult tissues, and enhanced protein levels were present in several non-neoplastic human skin disorders, implicating a crucial role for differentiation and homeostasis of multilayered epithelia. Here, we generated a mouse model in which Taps transgene expression is under the control of the human ubiquitin C promoter (UBC-Taps). Although no obvious phenotype was observed in normal skin development and homeostasis, these mice showed a significant delay in cutaneous wound closure compared with control animals. Shortly after re-epithelialization, we found an increase in keratinocytes in the stratum granulosum, which express Filaggrin, a late differentiation marker. A hypergranulosum-like phenotype with increased numbers of Filaggrin-positive keratinocytes was also observed in UBC-Taps mice after administration of TPA. In summary, these data show that aberrant Taps expression causes impaired skin regeneration and skin remodeling after cutaneous injury and chemically induced hyperplasia.
    Type of Publication: Journal article published
    PubMed ID: 20237492
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  • 7
    Keywords: CELLS ; GROWTH-FACTOR ; proliferation ; GENE-EXPRESSION ; SKIN ; C-JUN ; MAP KINASES ; MORPHOGENESIS ; SIGNAL-TRANSDUCTION PATHWAY ; EPIDERMAL-KERATINOCYTES
    Abstract: Previous studies demonstrated that fibroblast-derived and JUN-dependent soluble factors have a crucial role on keratinocyte proliferation and differentiation during cutaneous wound healing. Furthermore, mice with a deficiency in Jun N-terminal kinases (JNKs), JNK1 or JNK2, showed impaired skin development and delayed wound closure. To decipher the role of dermal JNK in keratinocyte behavior during these processes, we used a heterologous coculture model combining primary human keratinocytes and murine fibroblasts. Although cocultured JNK1/JNK2-deficient fibroblasts did not affect keratinocyte proliferation, temporal monitoring of the transcriptome of differentiating keratinocytes revealed that efficient keratinocyte differentiation not only requires the support by fibroblast-derived soluble factors, but is also critically dependent on JNK1 and JNK2 signaling in these cells. Moreover, we showed that the repertoire of fibroblast transcripts encoding secreted proteins is severely disarranged upon loss of JNK under the coculture conditions applied. Finally, our data demonstrate that efficient keratinocyte terminal differentiation requires constant presence of JNK-dependent and fibroblast-derived soluble factors. Taken together, our results imply that mesenchymal JNK has a pivotal role in the paracrine cross talk between dermal fibroblasts and epidermal keratinocytes during wound healing.
    Type of Publication: Journal article published
    PubMed ID: 24335928
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  • 8
    Keywords: CLONING ; GENE-EXPRESSION ; RECOGNITION ; SYNOVIAL FIBROBLASTS ; MATRIX METALLOPROTEINASES ; RHEUMATOID-ARTHRITIS ; INTERSTITIAL COLLAGENASE ; METALLOPROTEINASE 13-DEFICIENT MICE ; osteoarthritis ; CHONDROCYTES
    Abstract: Introduction: Matrix metalloproteinases (MMPs) are important in tissue remodelling. Here we investigate the role of collagenase-3 (MMP-13) in antibody-induced arthritis. Methods: For this study we employed the K/BxN serum-induced arthritis model. Arthritis was induced in C57BL/6 wild type (WT) and MMP-13-deficient (MMP-13(-/-)) mice by intraperitoneal injection of 200 mu l of K/BxN serum. Arthritis was assessed by measuring the ankle swelling. During the course of the experiments, mice were sacrificed every second day for histological examination of the ankle joints. Ankle sections were evaluated histologically for infiltration of inflammatory cells, pannus tissue formation and bone/cartilage destruction. Semi-quantitative PCR was used to determine MMP-13 expression levels in ankle joints of untreated and K/BxN serum-injected mice. Results: This study shows that MMP-13 is a regulator of inflammation. We observed increased expression of MMP-13 in ankle joints of WT mice during K/BxN serum-induced arthritis and both K/BxN serum-treated WT and MMP-13(-/-) mice developed progressive arthritis with a similar onset. However, MMP-13(-/-) mice showed significantly reduced disease over the whole arthritic period. Ankle joints of WT mice showed severe joint destruction with extensive inflammation and erosion of cartilage and bone. In contrast, MMP-13(-/-) mice displayed significantly decreased severity of arthritis (50% to 60%) as analyzed by clinical and histological scoring methods. Conclusions: MMP-13 deficiency acts to suppress the local inflammatory responses. Therefore, MMP-13 has a role in the pathogenesis of arthritis, suggesting MMP-13 is a potential therapeutic target.
    Type of Publication: Journal article published
    PubMed ID: 24369907
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  • 9
    Keywords: CARCINOGENESIS ; ANTIGEN ; KERATINOCYTES ; MOTILITY ; MESENCHYMAL TRANSITION ; PA2.26
    Abstract: The mucin-like transmembrane protein podoplanin (PDPN) is prominently represented in tumor-associated gene expression signatures of numerous types of cancer including SCC, and gain-of-function and knockdown approaches in tissue culture strongly suggested an important role of PDPN in cell proliferation, migration and adhesion. PDPN is absent during epidermal homeostasis but is highly expressed in basal keratinocytes during cutaneous wound healing. Enhanced motility of immortalized keratinocytes upon ectopic PDPN overexpression argue for wound healing defects upon podoplanin-deficiency in keratinocytes, however, in vivo data that unequivocally define the impact of PDPN by functional studies in a physiologically relevant system are still missing.
    Type of Publication: Journal article published
    PubMed ID: 26121181
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  • 10
    Keywords: ABLATION, ANGIOGENESIS, AP-1, BETA, CBF, CELL, CELLS, COMPLEX, COMPLEXES, CORE BINDING, DEFECT, EMBR
    Abstract: The molecular mechanism triggering the organization of endothelial cells (ECs) in multicellular tubules is mechanistically still poorly understood. We demonstrate that cell- autonomous endothelial functions of the AP-1 subunit JunB are required for proper endothelial morphogenesis both in vivo in mouse embryos with endothelial-specific ablation of JunB and in in vitro angiogenesis models. By cDNA microarray analysis, we identified core-binding factor beta (CBF beta), which together with the Runx proteins forms the heterodimeric core-binding transcription complex CBF, as a novel JunB target gene. In line with our findings, expression of the CBF target MMP-13 was impaired in JunB-deficient ECs. Reintroduction of CBF beta into JunB-deficient ECs rescued the tube formation defect and MMP-13 expression, indicating an important role for CBF beta in EC morphogenesis
    Type of Publication: Journal article published
    PubMed ID: 17158955
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