The Experts below are selected from a list of 798426 Experts worldwide ranked by ideXlab platform
Bevin P Engelward - One of the best experts on this subject based on the ideXlab platform.
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inflammation induced Cell Proliferation potentiates dna damage induced mutations in vivo
PLOS Genetics, 2015Co-Authors: Orsolya Kiraly, Guanyu Gong, Werner Olipitz, Sureshkumar Muthupalani, Bevin P EngelwardAbstract:Mutations are a critical driver of cancer initiation. While extensive studies have focused on exposure-induced mutations, few studies have explored the importance of tissue physiology as a modulator of mutation susceptibility in vivo. Of particular interest is inflammation, a known cancer risk factor relevant to chronic inflammatory diseases and pathogen-induced inflammation. Here, we used the fluorescent yellow direct repeat (FYDR) mice that harbor a reporter to detect misalignments during homologous recombination (HR), an important class of mutations. FYDR mice were exposed to cerulein, a potent inducer of pancreatic inflammation. We show that inflammation induces DSBs (γH2AX foci) and that several days later there is an increase in Cell Proliferation. While isolated bouts of inflammation did not induce HR, overlap between inflammation-induced DNA damage and inflammation-induced Cell Proliferation induced HR significantly. To study exogenously-induced DNA damage, animals were exposed to methylnitrosourea, a model alkylating agent that creates DNA lesions relevant to both environmental exposures and cancer chemotherapy. We found that exposure to alkylation damage induces HR, and importantly, that inflammation-induced Cell Proliferation and alkylation induce HR in a synergistic fashion. Taken together, these results show that, during an acute bout of inflammation, there is a kinetic barrier separating DNA damage from Cell Proliferation that protects against mutations, and that inflammation-induced Cell Proliferation greatly potentiates exposure-induced mutations. These studies demonstrate a fundamental mechanism by which inflammation can act synergistically with DNA damage to induce mutations that drive cancer and cancer recurrence.
Orsolya Kiraly - One of the best experts on this subject based on the ideXlab platform.
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inflammation induced Cell Proliferation potentiates dna damage induced mutations in vivo
PLOS Genetics, 2015Co-Authors: Orsolya Kiraly, Guanyu Gong, Werner Olipitz, Sureshkumar Muthupalani, Bevin P EngelwardAbstract:Mutations are a critical driver of cancer initiation. While extensive studies have focused on exposure-induced mutations, few studies have explored the importance of tissue physiology as a modulator of mutation susceptibility in vivo. Of particular interest is inflammation, a known cancer risk factor relevant to chronic inflammatory diseases and pathogen-induced inflammation. Here, we used the fluorescent yellow direct repeat (FYDR) mice that harbor a reporter to detect misalignments during homologous recombination (HR), an important class of mutations. FYDR mice were exposed to cerulein, a potent inducer of pancreatic inflammation. We show that inflammation induces DSBs (γH2AX foci) and that several days later there is an increase in Cell Proliferation. While isolated bouts of inflammation did not induce HR, overlap between inflammation-induced DNA damage and inflammation-induced Cell Proliferation induced HR significantly. To study exogenously-induced DNA damage, animals were exposed to methylnitrosourea, a model alkylating agent that creates DNA lesions relevant to both environmental exposures and cancer chemotherapy. We found that exposure to alkylation damage induces HR, and importantly, that inflammation-induced Cell Proliferation and alkylation induce HR in a synergistic fashion. Taken together, these results show that, during an acute bout of inflammation, there is a kinetic barrier separating DNA damage from Cell Proliferation that protects against mutations, and that inflammation-induced Cell Proliferation greatly potentiates exposure-induced mutations. These studies demonstrate a fundamental mechanism by which inflammation can act synergistically with DNA damage to induce mutations that drive cancer and cancer recurrence.
Lilianna Solnicakrezel - One of the best experts on this subject based on the ideXlab platform.
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stat3 cdc25a dependent Cell Proliferation promotes embryonic axis extension during zebrafish gastrulation
PLOS Genetics, 2017Co-Authors: Yinzi Liu, Diane S Sepich, Lilianna SolnicakrezelAbstract:Cell Proliferation has generally been considered dispensable for anteroposterior extension of embryonic axis during vertebrate gastrulation. Signal transducer and activator of transcription 3 (Stat3), a conserved controller of Cell Proliferation, survival and regeneration, is associated with human scoliosis, cancer and Hyper IgE Syndrome. Zebrafish Stat3 was proposed to govern convergence and extension gastrulation movements in part by promoting Wnt/Planar Cell Polarity (PCP) signaling, a conserved regulator of mediolaterally polarized Cell behaviors. Here, using zebrafish stat3 null mutants and pharmacological tools, we demonstrate that Cell Proliferation contributes to anteroposterior embryonic axis extension. Zebrafish embryos lacking maternal and zygotic Stat3 expression exhibit normal convergence movements and planar Cell polarity signaling, but transient axis elongation defect due to insufficient number of Cells resulting largely from reduced Cell Proliferation and increased apoptosis. Pharmacologic inhibition of Cell Proliferation during gastrulation phenocopied axis elongation defects. Stat3 regulates Cell Proliferation and axis extension in part via upregulation of Cdc25a expression during oogenesis. Accordingly, restoring Cdc25a expression in stat3 mutants partially suppressed Cell Proliferation and gastrulation defects. During later development, stat3 mutant zebrafish exhibit stunted growth, scoliosis, excessive inflammation, and fail to thrive, affording a genetic tool to study Stat3 function in vertebrate development, regeneration, and disease.
Toru Kita - One of the best experts on this subject based on the ideXlab platform.
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gas6 induces mesangial Cell Proliferation via latent transcription factor stat3
Journal of Biological Chemistry, 2001Co-Authors: Motoko Yanagita, Toru Nakano, Kazumasa Ohashi, Atsushi Fukatsu, Hidenori Arai, Kensaku Mizuno, Toru KitaAbstract:Abstract Mesangial Cell Proliferation is essential for the pathogenesis and progression of glomerular disease. Previously, we showed that Gas6 plays a pivotal role in mesangial Cell Proliferationin vitro and in vivo. In the present study, we identified downstream targets of Gas6 signaling to examine the role in mesangial Cell Proliferation in vitro and in vivo. We found that Gas6 tyrosine phosphorylates STAT3 (signal transducers and activators of transcription) with concomitant translocation to the nucleus and induces STAT3-dependent transcriptional activation in cultured mesangial Cells. Expressing dominant negative STAT3 inhibited Gas6-mediated transcriptional activation of STAT3 and abolished Gas6-induced mesangial Cell Proliferation. In a model of mesangial proliferative glomerulonephritis, STAT3 is phosphorylated in mesangial Cells, and its phosphorylation peaks at day 8 after the injection of anti-Thy1.1 antibody. Inhibition of Gas6 by warfarin and the extraCellular domain of its receptor, Axl, abolished phosphorylation of STAT3 in vivo. Thus, our in vitro and in vivo findings indicate that autocrine growth factor Gas6 induces mesangial Cell Proliferation via latent transcription factor STAT3. Therefore, STAT3 might be a new therapeutic target for kidney disease induced by mesangial Proliferation.
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gas6 regulates mesangial Cell Proliferation through axl in experimental glomerulonephritis
American Journal of Pathology, 2001Co-Authors: Motoko Yanagita, Toru Nakano, Kazumasa Ohashi, Atsushi Fukatsu, Brian Varnum, Kenji Ishii, Hidenori Arai, Kensaku Mizuno, Toru KitaAbstract:Proliferation of mesangial Cells is a hallmark of glomerular disease, and understanding its regulatory mechanism is clinically important. Previously, we demonstrated that the product of growth arrest-specific gene 6 (Gas6) stimulates mesangial Cell Proliferation through binding to its Cell-surface receptor Axl in vitro. We also showed that warfarin and the extraCellular domain of Axl conjugated with Fc portion of human IgG1 (Axl-Fc) inhibit mesangial Cell Proliferation by interfering the Gas6/Axl pathway in vitro. In the present study, therefore, we examined in vivo roles of Gas6 and Axl in an experimental model of mesangial proliferative glomerulonephritis induced by the injection of anti-Thy1.1 antibody (Thy1 GN). In Thy1 GN, expression of Gas6 and Axl was markedly increased in glomeruli, and paralleled the progression of mesangial Cell Proliferation. Administration of warfarin or daily injection of Axl-Fc inhibited mesangial Cell Proliferation, and abolished the induction of platelet-derived growth factor-B mRNA and protein in Thy1 GN. Moreover, the anti-proliferative effect of warfarin was achieved at lower concentrations than those in routine clinical use. These findings indicate that the Gas6/Axl pathway plays a key role in mesangial Cell Proliferation in vivo, and could be a potentially important therapeutic target for the treatment of renal disease.
Yinzi Liu - One of the best experts on this subject based on the ideXlab platform.
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stat3 cdc25a dependent Cell Proliferation promotes embryonic axis extension during zebrafish gastrulation
PLOS Genetics, 2017Co-Authors: Yinzi Liu, Diane S Sepich, Lilianna SolnicakrezelAbstract:Cell Proliferation has generally been considered dispensable for anteroposterior extension of embryonic axis during vertebrate gastrulation. Signal transducer and activator of transcription 3 (Stat3), a conserved controller of Cell Proliferation, survival and regeneration, is associated with human scoliosis, cancer and Hyper IgE Syndrome. Zebrafish Stat3 was proposed to govern convergence and extension gastrulation movements in part by promoting Wnt/Planar Cell Polarity (PCP) signaling, a conserved regulator of mediolaterally polarized Cell behaviors. Here, using zebrafish stat3 null mutants and pharmacological tools, we demonstrate that Cell Proliferation contributes to anteroposterior embryonic axis extension. Zebrafish embryos lacking maternal and zygotic Stat3 expression exhibit normal convergence movements and planar Cell polarity signaling, but transient axis elongation defect due to insufficient number of Cells resulting largely from reduced Cell Proliferation and increased apoptosis. Pharmacologic inhibition of Cell Proliferation during gastrulation phenocopied axis elongation defects. Stat3 regulates Cell Proliferation and axis extension in part via upregulation of Cdc25a expression during oogenesis. Accordingly, restoring Cdc25a expression in stat3 mutants partially suppressed Cell Proliferation and gastrulation defects. During later development, stat3 mutant zebrafish exhibit stunted growth, scoliosis, excessive inflammation, and fail to thrive, affording a genetic tool to study Stat3 function in vertebrate development, regeneration, and disease.
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Stat3/Cdc25a-dependent Cell Proliferation promotes embryonic axis extension during zebrafish gastrulation
2017Co-Authors: Yinzi Liu, Diane S Sepich, Lilianna Solnica-krezelAbstract:Cell Proliferation has generally been considered dispensable for anteroposterior extension of embryonic axis during vertebrate gastrulation. Signal transducer and activator of transcription 3 (Stat3), a conserved controller of Cell Proliferation, survival and regeneration, is associated with human scoliosis, cancer and Hyper IgE Syndrome. Zebrafish Stat3 was proposed to govern convergence and extension gastrulation movements in part by promoting Wnt/Planar Cell Polarity (PCP) signaling, a conserved regulator of mediolaterally polarized Cell behaviors. Here, using zebrafish stat3 null mutants and pharmacological tools, we demonstrate that Cell Proliferation contributes to anteroposterior embryonic axis extension. Zebrafish embryos lacking maternal and zygotic Stat3 expression exhibit normal convergence movements and planar Cell polarity signaling, but transient axis elongation defect due to insufficient number of Cells resulting largely from reduced Cell Proliferation and increased apoptosis. Pharmacologic inhibition of Cell Proliferation during gastrulation phenocopied axis elongation defects. Stat3 regulates Cell Proliferation and axis extension in part via upregulation of Cdc25a expression during oogenesis. Accordingly, restoring Cdc25a expression in stat3 mutants partially suppressed Cell Proliferation and gastrulation defects. During later development, stat3 mutant zebrafish exhibit stunted growth, scoliosis, excessive inflammation, and fail to thrive, affording a genetic tool to study Stat3 function in vertebrate development, regeneration, and disease.