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Peter Angel - One of the best experts on this subject based on the ideXlab platform.
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c-Jun and JUNB are essential for hypoglycemia-mediated VEGF induction.
Annals of the New York Academy of Sciences, 2006Co-Authors: Björn Textor, Peter Angel, Melanie Sator-schmitt, Karl Hartmut Richter, Marina Schorpp-kistnerAbstract:Physiological conditions like hypoxia or hypoglycemia trigger expression of VEGF, a key regulator of angiogenesis. To elucidate the molecular mechanism underlying the VEGF regulation of hypoglycemia, we investigated the role of AP-1 transcription factor subunits c-Jun and JUNB. Using c-jun(-/-) and JUNB(-/-) mouse embryonic fibroblasts, we demonstrate that both c-Jun and JUNB are required for the hypoglycemia-mediated induction of VEGF expression. This process is independent of the master regulator of hypoxic stress HIF-1, as HIF expression and stabilization are not affected by the loss of AP-1 subunits. Analysis of signaling cascades regulating c-Jun and/or JUNB activity and/or transcription upon hypoglycemia by application of specific inhibitors of protein kinase C (PKC) or extracellular signal-regulated kinase (ERK) signaling revealed that hypoglycemia-mediated induction of c-Jun is regulated via a PKCalpha-dependent signaling pathway. In contrast, JUNB is activated by the MAP kinase ERK for the AP-1 subunits c-Jun and JUNB to mediate VEGF regulaltion of hypoglycemia.
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Defective endochondral ossification in mice with strongly compromised expression of JUNB.
Journal of cell science, 2003Co-Authors: Jochen Hess, Marina Schorpp-kistner, Bettina Hartenstein, Sibylle Teurich, Dirk Schmidt, Peter AngelAbstract: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 p16INK4a, 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.
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Induction of the AP-1 members c-Jun and JUNB by TGF-β/Smad suppresses early Smad-driven gene activation
Oncogene, 2001Co-Authors: Franck Verrecchia, Peter Angel, Marina Schorpp-kistner, Charlotte Tacheau, Alain MauvielAbstract:Smad proteins transduce signals from TGF-β receptors and regulate transcription of target genes. Among the latter are c- jun and JUNB , which encode members of the AP-1 family of transcription factors. In this study, we have investigated the functional interactions of the Smad and AP-1 transcription factors in the context of Smad-specific gene transactivation in both fibroblasts and keratinocytes. We demonstrate that overexpression of either JUNB or c- jun prevents TGF-β- or Smad3-induced transactivation of the Smad-specific promoter construct (SBE)_4-Lux. Inversely, Smad-driven promoter transactivation by TGF-β/Smad is significantly enhanced when c- jun expression is abolished in HaCaT keratinocytes, and when JUNB expression is prevented in fibroblasts, consistent with the cell-type specific induction of jun members by TGF-β. We also demonstrate that Smad-specific gene transactivation in JUNB ^−/− mouse embryonic fibroblasts is significantly higher than in embryonic fibroblasts from the control parental mouse line, and that this difference is abolished by rescuing JUNB expression in JUNB ^−/− cells. Finally, we have determined that off-DNA interactions between Smad3 and both c-Jun and JUNB result in the reduction of Smad3/DNA interactions. From these results, we provide a model in which jun expression in response to the initial Smad cascade represents a negative feed-back mechanism counteracting Smad-driven gene transactivation.
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induction of the ap 1 members c jun and JUNB by tgf β smad suppresses early smad driven gene activation
Oncogene, 2001Co-Authors: Franck Verrecchia, Marina Schorppkistner, Peter Angel, Charlotte Tacheau, Alain MauvielAbstract:Smad proteins transduce signals from TGF-β receptors and regulate transcription of target genes. Among the latter are c-jun and JUNB, which encode members of the AP-1 family of transcription factors. In this study, we have investigated the functional interactions of the Smad and AP-1 transcription factors in the context of Smad-specific gene transactivation in both fibroblasts and keratinocytes. We demonstrate that overexpression of either JUNB or c-jun prevents TGF-β- or Smad3-induced transactivation of the Smad-specific promoter construct (SBE)4-Lux. Inversely, Smad-driven promoter transactivation by TGF-β/Smad is significantly enhanced when c-jun expression is abolished in HaCaT keratinocytes, and when JUNB expression is prevented in fibroblasts, consistent with the cell-type specific induction of jun members by TGF-β. We also demonstrate that Smad-specific gene transactivation in JUNB−/− mouse embryonic fibroblasts is significantly higher than in embryonic fibroblasts from the control parental mouse line, and that this difference is abolished by rescuing JUNB expression in JUNB−/− cells. Finally, we have determined that off-DNA interactions between Smad3 and both c-Jun and JUNB result in the reduction of Smad3/DNA interactions. From these results, we provide a model in which jun expression in response to the initial Smad cascade represents a negative feed-back mechanism counteracting Smad-driven gene transactivation.
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c jun and JUNB antagonistically control cytokine regulated mesenchymal epidermal interaction in skin
Cell, 2000Co-Authors: Axel Szabowski, Sven Andrecht, Marina Schorppkistner, Andrea Kolbus, Nicole Maasszabowski, Norbert E Fusenig, Peter AngelAbstract:Abstract Interactions between mesenchymal and epithelial cells are responsible for organogenesis and tissue homeostasis. This mutual cross-talk involves cell surface proteins and soluble factors, which are mostly the result of regulated transcription. To elucidate dimer-specific functions of the AP-1 family of transcription factors, we reconstituted skin by combining primary human keratinocytes and mouse wild-type, c-jun −/− , and JUNB −/− fibroblasts. We have discovered an antagonistic function of these AP-1 subunits in the fibroblast-mediated paracrine control of keratinocyte proliferation and differentiation, and traced this effect to the IL-1-dependent regulation of KGF and GM-CSF. These data suggest that the relative activation state of these AP-1 subunits in a non-cell-autonomous, transregulatory fashion directs regeneration of the epidermis and maintenance of tissue homeostasis in skin.
Alain Mauviel - One of the best experts on this subject based on the ideXlab platform.
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Induction of the AP-1 members c-Jun and JUNB by TGF-β/Smad suppresses early Smad-driven gene activation
Oncogene, 2001Co-Authors: Franck Verrecchia, Peter Angel, Marina Schorpp-kistner, Charlotte Tacheau, Alain MauvielAbstract:Smad proteins transduce signals from TGF-β receptors and regulate transcription of target genes. Among the latter are c- jun and JUNB , which encode members of the AP-1 family of transcription factors. In this study, we have investigated the functional interactions of the Smad and AP-1 transcription factors in the context of Smad-specific gene transactivation in both fibroblasts and keratinocytes. We demonstrate that overexpression of either JUNB or c- jun prevents TGF-β- or Smad3-induced transactivation of the Smad-specific promoter construct (SBE)_4-Lux. Inversely, Smad-driven promoter transactivation by TGF-β/Smad is significantly enhanced when c- jun expression is abolished in HaCaT keratinocytes, and when JUNB expression is prevented in fibroblasts, consistent with the cell-type specific induction of jun members by TGF-β. We also demonstrate that Smad-specific gene transactivation in JUNB ^−/− mouse embryonic fibroblasts is significantly higher than in embryonic fibroblasts from the control parental mouse line, and that this difference is abolished by rescuing JUNB expression in JUNB ^−/− cells. Finally, we have determined that off-DNA interactions between Smad3 and both c-Jun and JUNB result in the reduction of Smad3/DNA interactions. From these results, we provide a model in which jun expression in response to the initial Smad cascade represents a negative feed-back mechanism counteracting Smad-driven gene transactivation.
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induction of the ap 1 members c jun and JUNB by tgf β smad suppresses early smad driven gene activation
Oncogene, 2001Co-Authors: Franck Verrecchia, Marina Schorppkistner, Peter Angel, Charlotte Tacheau, Alain MauvielAbstract:Smad proteins transduce signals from TGF-β receptors and regulate transcription of target genes. Among the latter are c-jun and JUNB, which encode members of the AP-1 family of transcription factors. In this study, we have investigated the functional interactions of the Smad and AP-1 transcription factors in the context of Smad-specific gene transactivation in both fibroblasts and keratinocytes. We demonstrate that overexpression of either JUNB or c-jun prevents TGF-β- or Smad3-induced transactivation of the Smad-specific promoter construct (SBE)4-Lux. Inversely, Smad-driven promoter transactivation by TGF-β/Smad is significantly enhanced when c-jun expression is abolished in HaCaT keratinocytes, and when JUNB expression is prevented in fibroblasts, consistent with the cell-type specific induction of jun members by TGF-β. We also demonstrate that Smad-specific gene transactivation in JUNB−/− mouse embryonic fibroblasts is significantly higher than in embryonic fibroblasts from the control parental mouse line, and that this difference is abolished by rescuing JUNB expression in JUNB−/− cells. Finally, we have determined that off-DNA interactions between Smad3 and both c-Jun and JUNB result in the reduction of Smad3/DNA interactions. From these results, we provide a model in which jun expression in response to the initial Smad cascade represents a negative feed-back mechanism counteracting Smad-driven gene transactivation.
Erwin F. Wagner - One of the best experts on this subject based on the ideXlab platform.
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the ap 1 transcription factor JUNB promotes multiple myeloma mm cell proliferation survival and drug resistance in the bone marrow microenvironment
Blood, 2014Co-Authors: Fengjuan Fan, Erwin F. Wagner, Latifa Bakiri, Sonia Vallet, Martin Sattler, Giovanni Tonon, Muhammad Hasan Bashari, Hartmut Goldschmidt, Dirk Jaeger, Klaus PodarAbstract:MEK/ERK and NF-kB signaling pathways have been reported to play a key role in multiple myeloma (MM) survival, proliferation and drug resistance. These pathways regulate the activity of numerous transcription factors. For example, the activator protein-1 (AP-1) transcription factor has been implicated in a multitude of physiologic processes, but also tumorigenesis. However, the function of AP-1 in MM is largely unknown. Our data show a vast variety of AP-1 (c-Jun, JUNB, JunD, c-Maf and c-Fos) expression levels in MM cells. Importantly, co-culture of MM cells with bone marrow stromal cells (BMSCs), i.e. isotypic primary BMSCs as well as BMSC lines KM-105 and HS-27A, rapidly and strongly induces expression of JUNB, but not other AP-1 members. Previous studies have shown that JUNB exerts opposite functions depending on the cellular origin and the physiopathological context. For example, it serves as a gatekeeper in acute and chronic myeloid leukemia, but as a positive regulator in Hodgkin9s lymphomas and anaplastic large cell lymphomas. The relevance of JUNB activity in MM growth, survival and drug resistance is elusive. First, our data demonstrate that induction of JUNB is predominantly mediated by soluble factors secreted by BMSCs rather than direct MM-BMSC contact. Indeed, using cytokine arrays, we identified IL-6 among the most potent factors that trigger JUNB expression. Mechanistically, JUNB upregulation occurs at both transcriptional as well as translational level. Pharmacologic inhibition was used next in order to identify upstream signaling pathways, which mediate BMSC- induced JUNB upregulation in MM cells. Our data show that activation of MEK/ERK or NF-kB is required for induction of JUNB expression and AP-1 transcriptional activity. To delineate the specific functional role of JUNB in MM pathogenesis, we transduced MM cells with pLKO.1-JUNB shRNA or pLKO.1-scrambled shRNA (SCR). After puromycin- selection, effects of JUNB knockdown on MM proliferation, survival and drug resistance were analyzed by 3H-thymidine incorporation, flow cytometry and western blot. Indeed, we observed significant inhibition of proliferation in MM/ JUNB shRNA (decreased to ~ 25 – 40 %, p Furthermore, 4-hydroxytamoxifen (4-OHT) treatment of MM cell lines stably transduced with pMSCV-JUNB-ER-IRES-GFP but not pMSCV-IRES-GFP induced significant AP-1 luciferase activity (~ 3.3 fold, p 1000 MM patient samples of different prognostic groups were compared to samples from healthy donors using the gene set enrichment analysis (GSEA). Our results further support a key role for JUNB in MM pathogenesis. In summary, our data demonstrate for the first time an important role of JUNB/AP-1 in MM tumorigenesis and strongly propose it as a novel therapeutic target in MM. Disclosures No relevant conflicts of interest to declare.
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Targeting c-Jun and JUNB proteins as potential anticancer cell therapy
Oncogene, 2007Co-Authors: Esteban Nicolas Gurzov, Erwin F. Wagner, Latifa Bakiri, J M Alfaro, Marta IzquierdoAbstract:The activating protein-1 transcription factor, in particular the Jun proteins play critical roles in the regulation of cell proliferation and tumor progression. To study the potential clinical relevance of interfering with JUNB expression, we generated retroviruses expressing short hairpin RNA. Reduction of JUNB levels causes increased proliferation and tumorigenicity in wild-type murine fibroblasts, whereas in c-Jun knockout cells p53-independent cell cycle arrest and apoptosis are induced. Using melanoma-derived B16-F10 cancer cells the combination of JUNB knockdown and c-Jun/JNK inactivation leads to cell cycle arrest and apoptosis-inducing factor-dependent apoptosis. Furthermore, the combined treatment extends survival of mice inoculated with the tumor cells. These results indicate that in the absence of c-Jun, JUNB can act as a tumor promoter and inactivation of both, c-Jun and JUNB, could provide a valuable strategy for antitumor intervention.
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JUNB is a gatekeeper for B-lymphoid leukemia
Oncogene, 2007Co-Authors: Rene G. Ott, Erwin F. Wagner, Olivia Simma, Karoline Kollmann, Eva Weisz, Eva-maria Zebedin, Marina Schorpp-kistner, Gerwin Heller, S Zöchbauer, Michael FreissmuthAbstract:Loss of JUNB has been observed in human leukemia and lymphoma, but it remains unknown, whether this loss is relevant to disease progression. Here, we investigated the consequences of JUNB deficiency using Abelson-induced B-lymphoid leukemia as a model system. Mice deficient in JUNB expression succumbed to Abelson-induced leukemia with increased incidence and significantly reduced latency. Similarly, bcr/abl p185-transformed JUNB-deficient (JUNBΔ/Δ) cells induced leukemia in RAG2−/− mice displaying a more malignant phenotype. These observations indicated that cell intrinsic effects within the JUNBΔ/Δ tumor cells accounted for the accelerated leukemia development. Indeed, explantated bcr/abl p185 transformed JUNBΔ/Δ cells proliferated faster than the control cells. The proliferative advantage emerged slowly after the initial transformation process and was associated with increased expression levels of the cell cycle kinase cdk6 and with decreased levels of the cell cycle inhibitor p16INK4a. These alterations were due to irreversible reprogramming of the cell, because – once established – accelerated disease induced by JUNBΔ/Δ cells was not reverted by re-introducing JUNB. Consistent with this observation, we found that the p16 promoter was methylated. Thus, JUNB functions as a gatekeeper during tumor evolution. In its absence, transformed leukemic cells acquire an enhanced proliferative capacity, which presages a more malignant disease.
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JUNB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells
Cell, 2004Co-Authors: Emmanuelle Passegue, Erwin F. Wagner, Irving L WeissmanAbstract:The AP-1 transcription factor JUNB is a transcriptional regulator of myelopoiesis. Inactivation of JUNB in postnatal mice results in a myeloproliferative disorder (MPD) resembling early human chronic myelogenous leukemia (CML). Here, we show that JUNB regulates the numbers of hematopoietic stem cells (HSC). JUNB overexpression decreases the frequency of long-term HSC (LT-HSC), while JUNB inactivation specifically expands the numbers of LT-HSC and granulocyte/macrophage progenitors (GMP) resulting in chronic MPD. Further, we demonstrate that JUNB inactivation must take place in LT-HSC, and not at later stages of myelopoiesis, to induce MPD and that only JUNB-deficient LT-HSC are capable of transplanting the MPD to recipient mice. These results demonstrate a stem cell-specific role for JUNB in normal and leukemic hematopoiesis and provide experimental evidence that leukemic stem cells (LSC) can reside at the LT-HSC stage of development in a mouse model of MPD.
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JUNB can substitute for Jun in mouse development and cell proliferation.
Nature genetics, 2002Co-Authors: Emmanuelle Passegue, Wolfram Jochum, Axel Behrens, Romeo Ricci, Erwin F. WagnerAbstract:The Jun and JUNB components of the AP-1 transcription factor are known to have antagonistic functions. Here we show, by a knock-in strategy and a transgenic complementation approach, that JUNB can substitute for absence of Jun during mouse development. JUNB can rescue both liver and cardiac defects in Jun-null mice in a manner dependent on gene dosage. JUNB restores the expression of genes regulated by Jun/Fos, but not those regulated by Jun/ATF, thereby rescuing Jun-dependent defects in vivo as well as in primary fibroblasts and fetal hepatoblasts in vitro. Thus, the transcriptionally less active JUNB has the potential to substitute for Jun, indicating that the spatial and temporal regulation of expression of the transcription factor AP-1 may be more important than the coding sequence of its components.
Marina Schorpp-kistner - One of the best experts on this subject based on the ideXlab platform.
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JUNB is a gatekeeper for B-lymphoid leukemia
Oncogene, 2007Co-Authors: Rene G. Ott, Erwin F. Wagner, Olivia Simma, Karoline Kollmann, Eva Weisz, Eva-maria Zebedin, Marina Schorpp-kistner, Gerwin Heller, S Zöchbauer, Michael FreissmuthAbstract:Loss of JUNB has been observed in human leukemia and lymphoma, but it remains unknown, whether this loss is relevant to disease progression. Here, we investigated the consequences of JUNB deficiency using Abelson-induced B-lymphoid leukemia as a model system. Mice deficient in JUNB expression succumbed to Abelson-induced leukemia with increased incidence and significantly reduced latency. Similarly, bcr/abl p185-transformed JUNB-deficient (JUNBΔ/Δ) cells induced leukemia in RAG2−/− mice displaying a more malignant phenotype. These observations indicated that cell intrinsic effects within the JUNBΔ/Δ tumor cells accounted for the accelerated leukemia development. Indeed, explantated bcr/abl p185 transformed JUNBΔ/Δ cells proliferated faster than the control cells. The proliferative advantage emerged slowly after the initial transformation process and was associated with increased expression levels of the cell cycle kinase cdk6 and with decreased levels of the cell cycle inhibitor p16INK4a. These alterations were due to irreversible reprogramming of the cell, because – once established – accelerated disease induced by JUNBΔ/Δ cells was not reverted by re-introducing JUNB. Consistent with this observation, we found that the p16 promoter was methylated. Thus, JUNB functions as a gatekeeper during tumor evolution. In its absence, transformed leukemic cells acquire an enhanced proliferative capacity, which presages a more malignant disease.
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c-Jun and JUNB are essential for hypoglycemia-mediated VEGF induction.
Annals of the New York Academy of Sciences, 2006Co-Authors: Björn Textor, Peter Angel, Melanie Sator-schmitt, Karl Hartmut Richter, Marina Schorpp-kistnerAbstract:Physiological conditions like hypoxia or hypoglycemia trigger expression of VEGF, a key regulator of angiogenesis. To elucidate the molecular mechanism underlying the VEGF regulation of hypoglycemia, we investigated the role of AP-1 transcription factor subunits c-Jun and JUNB. Using c-jun(-/-) and JUNB(-/-) mouse embryonic fibroblasts, we demonstrate that both c-Jun and JUNB are required for the hypoglycemia-mediated induction of VEGF expression. This process is independent of the master regulator of hypoxic stress HIF-1, as HIF expression and stabilization are not affected by the loss of AP-1 subunits. Analysis of signaling cascades regulating c-Jun and/or JUNB activity and/or transcription upon hypoglycemia by application of specific inhibitors of protein kinase C (PKC) or extracellular signal-regulated kinase (ERK) signaling revealed that hypoglycemia-mediated induction of c-Jun is regulated via a PKCalpha-dependent signaling pathway. In contrast, JUNB is activated by the MAP kinase ERK for the AP-1 subunits c-Jun and JUNB to mediate VEGF regulaltion of hypoglycemia.
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Defective endochondral ossification in mice with strongly compromised expression of JUNB.
Journal of cell science, 2003Co-Authors: Jochen Hess, Marina Schorpp-kistner, Bettina Hartenstein, Sibylle Teurich, Dirk Schmidt, Peter AngelAbstract: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 p16INK4a, 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.
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Induction of the AP-1 members c-Jun and JUNB by TGF-β/Smad suppresses early Smad-driven gene activation
Oncogene, 2001Co-Authors: Franck Verrecchia, Peter Angel, Marina Schorpp-kistner, Charlotte Tacheau, Alain MauvielAbstract:Smad proteins transduce signals from TGF-β receptors and regulate transcription of target genes. Among the latter are c- jun and JUNB , which encode members of the AP-1 family of transcription factors. In this study, we have investigated the functional interactions of the Smad and AP-1 transcription factors in the context of Smad-specific gene transactivation in both fibroblasts and keratinocytes. We demonstrate that overexpression of either JUNB or c- jun prevents TGF-β- or Smad3-induced transactivation of the Smad-specific promoter construct (SBE)_4-Lux. Inversely, Smad-driven promoter transactivation by TGF-β/Smad is significantly enhanced when c- jun expression is abolished in HaCaT keratinocytes, and when JUNB expression is prevented in fibroblasts, consistent with the cell-type specific induction of jun members by TGF-β. We also demonstrate that Smad-specific gene transactivation in JUNB ^−/− mouse embryonic fibroblasts is significantly higher than in embryonic fibroblasts from the control parental mouse line, and that this difference is abolished by rescuing JUNB expression in JUNB ^−/− cells. Finally, we have determined that off-DNA interactions between Smad3 and both c-Jun and JUNB result in the reduction of Smad3/DNA interactions. From these results, we provide a model in which jun expression in response to the initial Smad cascade represents a negative feed-back mechanism counteracting Smad-driven gene transactivation.
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Chronic Myeloid Leukemia with Increased Granulocyte Progenitors in Mice Lacking JUNB Expression in the Myeloid Lineage
Cell, 2001Co-Authors: Emmanuelle Passegue, Marina Schorpp-kistner, Wolfram Jochum, Uta Möhle-steinlein, Erwin F. WagnerAbstract:The functions of JUNB during myelopoiesis were studied in vivo. Transgenic mice specifically lacking JUNB expression in the myeloid lineage (JUNB(-/-)Ubi-JUNB mice) develop a transplantable myeloproliferative disease eventually progressing to blast crisis, which resembles human chronic myeloid leukemia. Similarly, mice reconstituted with ES cell-derived JUNB-/- fetal liver cells also develop a myeloproliferative disease. In both cases, the absence of JUNB expression results in increased numbers of granulocyte progenitors, which display enhanced GM-CSF-mediated proliferation and extended survival, associated with changes in the expression levels of the GM-CSFalpha receptor, the anti-apoptotic proteins Bcl2 and Bclx, and the cell cycle regulators p16(INK4a) and c-Jun. Importantly, ectopic expression of JUNB fully reverts the immature and hyperproliferative phenotype of JUNB-deficient myeloid cells. These results identify JUNB as a key transcriptional regulator of myelopoiesis and a potential tumor suppressor gene.
Franck Verrecchia - One of the best experts on this subject based on the ideXlab platform.
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Induction of the AP-1 members c-Jun and JUNB by TGF-β/Smad suppresses early Smad-driven gene activation
Oncogene, 2001Co-Authors: Franck Verrecchia, Peter Angel, Marina Schorpp-kistner, Charlotte Tacheau, Alain MauvielAbstract:Smad proteins transduce signals from TGF-β receptors and regulate transcription of target genes. Among the latter are c- jun and JUNB , which encode members of the AP-1 family of transcription factors. In this study, we have investigated the functional interactions of the Smad and AP-1 transcription factors in the context of Smad-specific gene transactivation in both fibroblasts and keratinocytes. We demonstrate that overexpression of either JUNB or c- jun prevents TGF-β- or Smad3-induced transactivation of the Smad-specific promoter construct (SBE)_4-Lux. Inversely, Smad-driven promoter transactivation by TGF-β/Smad is significantly enhanced when c- jun expression is abolished in HaCaT keratinocytes, and when JUNB expression is prevented in fibroblasts, consistent with the cell-type specific induction of jun members by TGF-β. We also demonstrate that Smad-specific gene transactivation in JUNB ^−/− mouse embryonic fibroblasts is significantly higher than in embryonic fibroblasts from the control parental mouse line, and that this difference is abolished by rescuing JUNB expression in JUNB ^−/− cells. Finally, we have determined that off-DNA interactions between Smad3 and both c-Jun and JUNB result in the reduction of Smad3/DNA interactions. From these results, we provide a model in which jun expression in response to the initial Smad cascade represents a negative feed-back mechanism counteracting Smad-driven gene transactivation.
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induction of the ap 1 members c jun and JUNB by tgf β smad suppresses early smad driven gene activation
Oncogene, 2001Co-Authors: Franck Verrecchia, Marina Schorppkistner, Peter Angel, Charlotte Tacheau, Alain MauvielAbstract:Smad proteins transduce signals from TGF-β receptors and regulate transcription of target genes. Among the latter are c-jun and JUNB, which encode members of the AP-1 family of transcription factors. In this study, we have investigated the functional interactions of the Smad and AP-1 transcription factors in the context of Smad-specific gene transactivation in both fibroblasts and keratinocytes. We demonstrate that overexpression of either JUNB or c-jun prevents TGF-β- or Smad3-induced transactivation of the Smad-specific promoter construct (SBE)4-Lux. Inversely, Smad-driven promoter transactivation by TGF-β/Smad is significantly enhanced when c-jun expression is abolished in HaCaT keratinocytes, and when JUNB expression is prevented in fibroblasts, consistent with the cell-type specific induction of jun members by TGF-β. We also demonstrate that Smad-specific gene transactivation in JUNB−/− mouse embryonic fibroblasts is significantly higher than in embryonic fibroblasts from the control parental mouse line, and that this difference is abolished by rescuing JUNB expression in JUNB−/− cells. Finally, we have determined that off-DNA interactions between Smad3 and both c-Jun and JUNB result in the reduction of Smad3/DNA interactions. From these results, we provide a model in which jun expression in response to the initial Smad cascade represents a negative feed-back mechanism counteracting Smad-driven gene transactivation.
