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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: 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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  • 3
    Keywords: brain ; CELLS ; EXPRESSION ; GROWTH ; CELL ; DENSITY ; liver ; METABOLISM ; TISSUE ; MICE ; MECHANISM ; SERA ; REDUCTION ; BODY-WEIGHT ; TISSUES ; mechanisms ; TYPE-1 ; ALPHA ; DELETION ; MOUSE ; MUTANT ; TRANSGENIC MICE ; DISRUPTION ; MUSCLE ; PHENOTYPE ; BINDING-PROTEINS ; BODY ; FACTOR-I ; LACKING ; SERUM ; BODIES ; IGF-I ; ENDOCRINE ; LEADS ; WEIGHT ; MICE LACKING ; body weight ; development ; GROWTH-FACTOR-I ; LEVEL ; analysis ; SIZE ; USA ; function ; DEFICIENT ; CIRCULATING LEVELS ; conditional mutant ; insulin-like growth factor-I ; BIOLOGICAL-FLUIDS ; INDEPENDENT MECHANISMS ; LUNG DEVELOPMENT ; MINERAL DENSITY
    Abstract: IGF-I acts through endocrine and local, autocrine/paracrine routes. Disruption of both endocrine and local IGF-I action leads to neonatal lethality and impaired growth in various tissues including bone; however, the severity of growth and skeletal phenotype caused by disruption of endocrine IGF-I action is far less than with total IGF-I disruption. Based on these data and the fact that bone cells express IGF-I in high abundance, we and others predicted that locally produced IGF-I is also critical in regulating growth and bone accretion. To determine the role of local IGF-I, type 1 alpha 2 collagen-Cre mice were crossed with IGF-I loxP mice to generate Cre+ (conditional mutant) and Cre-(control) loxP homozygous mice. Surprisingly, approximately 40-50% of the conditional mutants died at birth, which is similar to total IGF-I disruption, but not observed in mice lacking circulating IGF-I. Expression of IGF-I in bone and muscle but not liver and brain was significantly decreased in the conditional mutant. Accordingly, circulating levels of serum IGF-I were also not affected. Disruption of local IGF-I dramatically reduced body weight 28-37%, femur areal bone mineral density 10-25%, and femur bone size 18-24% in growing mice. In addition, mineralization was reduced as early as during embryonic development. Consistently, histomorphometric analysis determined impaired osteoblast function as demonstrated by reduced mineral apposition rate (14-30%) and bone formation rate (35-57%). In conclusion, both local and endocrine IGF-I actions are involved in regulating growth of various tissues including bone, but they act via different mechanisms
    Type of Publication: Journal article published
    PubMed ID: 17717052
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  • 4
    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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  • 5
    Keywords: CELL, CELL-LINE, DIFFERENTIATION, GENE, gene array, PHENOTYPE, REVEALS
    Abstract: Differentiation of undifferentiated mammary epithelial stem and/or progenitor cells results in the production of luminal-ductal and myoepithelial cells in the young animal and upon pregnancy, the production of luminal alveolar cells. A few key regulators of differentiation have been identified, though it is not known yet how these proteins function together to achieve their well-orchestrated products. In an effort to identify regulators of early differentiation, we screened the NIA 15k gene array of 15,247 developmentally expressed genes using mouse mammary epithelial HC11 cells as a model of differentiation. We have confirmed a number of genes preferentially expressed in the undifferentiated cells (Lgals1, Ran, Jam-A and Bmpr1a) and in those induced to undergo differentiation (Id1, Nfkbiz, Trib1, Rps21, Ier3). Using antibodies to the proteins encoded by Lgals1, and Jam-A, we confirmed that their proteins levels were higher in the undifferentiated cells. Although the amounts of bone morphogenetic protein receptor-1A (BMPR1A) protein were present at all stages, we found the activity of its downstream signal transduction pathway, as measured by the presence of phosphorylated-SMAD1, -SMAD5, and -SMAD8, is elevated in undifferentiated cells and decreases in fully differentiated cells. This evidence supports that the BMPR1A pathway functions primarily in undifferentiated mammary epithelial cells. We have identified a number of genes, of known and unknown function, that are candidates for the maintenance of the undifferentiated phenotype and for early regulators of mammary alveolar cell differentiation.
    Type of Publication: Journal article published
    PubMed ID: 19523745
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  • 6
    Keywords: CELLS ; EXPRESSION ; IN-VITRO ; CELL ; Germany ; VIVO ; SITE ; SITES ; PROTEIN ; COMPONENTS ; CULTURED-CELLS ; COMPLEX ; COMPLEXES ; DNA ; KERATINOCYTES ; papillomavirus ; PARTICLES ; virus ; REQUIRES ; VIRUS-LIKE PARTICLES ; WILD-TYPE ; MONOCLONAL-ANTIBODIES ; DNA-REPLICATION ; L1 ; OVEREXPRESSION ; GREEN FLUORESCENT PROTEIN ; PML ; HEAT-SHOCK-PROTEIN ; HSP70 CHAPERONE ACTIVITY ; TYPE-33 ; VIRAL-PROTEINS
    Abstract: Minor capsid protein L2 of papillomaviruses plays an essential role in virus assembly by recruiting viral components to PML bodies, the proposed sites of virus morphogenesis. We demonstrate here that the function of L2 in virus assembly requires the chaperone Hsc70. Hsc70 was found dispersed in naturally infected keratinocytes and cultured cells. A dramatic relocation of Hsc70 from the cytoplasm to PML bodies was induced in these cells by L2 expression. Hsc70-L2 complex formation was confirmed by coimmunoprecipitation. The complex was modulated by the cochaperones Hip and Bag-1, which stabilize and destabilize Hsc70-substrate complexes, respectively. Cytoplasmic depletion of Hsc70 caused retention of wild-type and N-terminally truncated L2, but not of C-terminally truncated L2, in the cytoplasm. This retention was partially reversed by overexpression of Hsc70 fused to green fluorescent protein but not by ATPase-negative Hsc70. Hsc70 associated with L1-L2 virus-like particles (VLPs) but not with VLPs composed either of L1 alone or of L1 and C-terminally truncated L2. Moreover, displacement of Hsc70 from L1-L2 VLPs by encapsidation of DNA, generating pseudovirions, was found. These data indicate that Hsc70 transiently associates with viral capsids during the integration of L2, possibly via the L2 C terminus. Completion of virus assembly results in displacement of Hsc70 from virions
    Type of Publication: Journal article published
    PubMed ID: 15140951
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  • 7
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; GROWTH-FACTOR ; IN-VITRO ; FACTOR RECEPTOR ; IN-VIVO ; VITRO ; DISEASE ; GENE ; PROTEIN ; PROTEINS ; MICE ; ARTHRITIS ; AP-1 ; tumour ; CONTRAST ; KERATINOCYTES ; SKIN ; T-CELLS ; C-JUN ; DOWN-REGULATION ; SUSCEPTIBILITY ; DELETION ; TRANSGENIC MICE ; LESIONS ; REGION ; B-CELLS ; STEM-CELLS ; Jun ; PHENOTYPE ; MOUSE MODEL ; epidermis ; NEUTROPHILS ; PSORIASIS ; molecular ; ADULT ; RE ; keratinocyte ; development ; RECRUITS ; NECROSIS-FACTOR ; signalling ; ACTIVATED KERATINOCYTES ; MICE LACKING JUNB
    Abstract: Psoriasis is a frequent, inflammatory disease of skin and joints with considerable morbidity. Here we report that in psoriatic lesions, epidermal keratinocytes have decreased expression of JunB, a gene localized in the psoriasis susceptibility region PSORS6. Likewise, inducible epidermal deletion of JunB and its functional companion c-Jun in adult mice leads ( within two weeks) to a phenotype resembling the histological and molecular hallmarks of psoriasis, including arthritic lesions. In contrast to the skin phenotype, the development of arthritic lesions requires T and B cells and signalling through tumour necrosis factor receptor 1 ( TNFR1). Prior to the disease onset, two chemotactic proteins (S100A8 and S100A9) previously mapped to the psoriasis susceptibility region PSORS4, are strongly induced in mutant keratinocytes in vivo and in vitro. We propose that the abrogation of JunB/activator protein 1 (AP-1) in keratinocytes triggers chemokine/cytokine expression, which recruits neutrophils and macrophages to the epidermis thereby contributing to the phenotypic changes observed in psoriasis. Thus, these data support the hypothesis that epidermal alterations are sufficient to initiate both skin lesions and arthritis in psoriasis
    Type of Publication: Journal article published
    PubMed ID: 16163348
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  • 8
    Keywords: CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; proliferation ; Germany ; VITRO ; SYSTEM ; transcription ; DIFFERENTIATION ; TISSUE ; MICE ; ACTIVATION ; COMPLEX ; COMPLEXES ; FAMILY ; TRANSCRIPTION FACTOR ; KERATINOCYTES ; SKIN ; C-JUN ; fibroblasts ; treatment ; SIGNAL ; TRANSGENIC MICE ; STRESS ; REPAIR ; EPITHELIAL-CELLS ; KINETICS ; REGULATOR ; COLONY-STIMULATING FACTOR ; INTERCELLULAR COMMUNICATION ; TISSUE-SPECIFIC EXPRESSION ; inflammation ; CYTOKINE ; FAMILIES ; MICE LACKING ; KERATINOCYTE DIFFERENTIATION ; IMMUNE-SYSTEM ; LEVEL ; REGULATED GENE ; macrophage ; inflammatory cells ; COLLAGEN GEL ; GROWTH-STIMULATORY ACTIVITY ; TRANSCRIPTION FACTOR AP-1
    Abstract: The cutaneous response to injury and stress comprises a temporary change in the balance between epidermal proliferation and differentiation as well as an activation of the immune system. Soluble factors play an important role in the regulation of these complex processes by coordinating the intercellular communication between keratinocytes, fibroblasts, and inflammatory cells. In this study, we demonstrate that JunB, a member of the activator protein-1 transcription factor family, is an important regulator of cytokine expression and thus critically involved in the cutaneous response to injury and stress. Mice lacking JunB in the skin develop normally, indicating that JunB is neither required for cutaneous organogenesis, nor homeostasis. However, upon wounding and treatment with the phorbol ester 12-O-decanoyl-phorbol-13-acetate, JunB-deficiency in the skin likewise resulted in pronounced epidermal hyperproliferation, disturbed differentiation, and prolonged inflammation. Furthermore, delayed tissue remodelling was observed during wound healing. These phenotypic skin abnormalities were associated with JunB-dependent alterations in expression levels and kinetics of important mediators of wound repair, such as granulocyte macrophage colony-stimulating factor, growth-regulated protein-1, macrophage inflammatory protein-2, and lipocalin-2 in both the dermal and epidermal compartment of the skin, and a reduced ability of wound contraction of mutant dermal fibroblasts in vitro
    Type of Publication: Journal article published
    PubMed ID: 16439969
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  • 9
    Keywords: IN-VIVO ; fibroblasts ; OXIDATIVE STRESS ; OSTEOPOROSIS ; HYDROGEN-PEROXIDE ; DNA MUTATIONS ; SKELETAL-MUSCLE MASS ; AGED HUMAN SKIN ; BONE MASS ; SARCOPENIA
    Abstract: P〉The free radical theory of aging postulates that the production of mitochondrial reactive oxygen species is the major determinant of aging and lifespan. Its role in aging of the connective tissue has not yet been established, even though the incidence of aging-related disorders in connective tissue-rich organs is high, causing major disability in the elderly. We have now addressed this question experimentally by creating mice with conditional deficiency of the mitochondrial manganese superoxide dismutase in fibroblasts and other mesenchyme-derived cells of connective tissues in all organs. Here, we have shown for the first time that the connective tissue-specific lack of superoxide anion detoxification in the mitochondria results in reduced lifespan and premature onset of aging-related phenotypes such as weight loss, skin atrophy, kyphosis (curvature of the spine), osteoporosis and muscle degeneration in mutant mice. Increase in p16INK4a, a robust in vivo marker for fibroblast aging, may contribute to the observed phenotype. This novel model is particularly suited to decipher the underlying mechanisms and to develop hopefully novel connective tissue-specific anti-aging strategies.
    Type of Publication: Journal article published
    PubMed ID: 21108731
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  • 10
    Keywords: GROWTH-FACTOR RECEPTOR ; DUAL ROLE ; CAPSID PROTEIN ; GENE-THERAPY ; TRANSDUCTION EFFICIENCY ; MUTATIONAL ANALYSIS ; MURINE FIBROBLASTS ; PHOSPHOLIPASE-A2 ACTIVITY ; ENDOSOMAL MEMBRANE ; CELL ENTRY
    Abstract: Adeno-associated virus type 2 (AAV2) has gained much interest as a gene delivery vector. A hallmark of AAV2-mediated gene transfer is an intracellular conformational change of the virus capsid, leading to the exposure of infection-relevant protein domains. These protein domains, which are located on the N-terminal portion of the structural proteins VP1 and VP2, include a catalytic phospholipase A(2) domain and three clusters of basic amino acids. We have identified additional protein sequence motifs located on the VP1/2 N terminus that also proved to be obligatory for virus infectivity. These motifs include signals that are known to be involved in protein interaction, endosomal sorting and signal transduction in eukaryotic cells. Among different AAV serotypes they are highly conserved and mutation of critical amino acids of the respective motifs led to a severe infection-deficient phenotype. In particular, mutation of a YXXQ-sequence motif significantly reduced accumulation of virus capsids around the nucleus in comparison to wild-type AAV2. Interestingly, intracellular trafficking of AAV2 was shown to be independent of PLA(2) activity. Moreover, mutation of three PDZ-binding motifs, which are located consecutively at the very tip of the VP1 N terminus, revealed a nuclear transport-defective phenotype, suggesting a role in nuclear uptake of the virus through an as-yet-unknown mechanism.
    Type of Publication: Journal article published
    PubMed ID: 22696661
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