Mechanisms of KGF Mediated Signaling in Pancreatic Duct Cell Proliferation and Differentiation
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{"title"=>"Mechanisms of KGF mediated signaling in pancreatic duct cell proliferation and differentiation", "type"=>"journal", "authors"=>[{"first_name"=>"Benjamin", "last_name"=>"Uzan", "scopus_author_id"=>"23502565200"}, {"first_name"=>"Florence", "last_name"=>"Figeac", "scopus_author_id"=>"26421187500"}, {"first_name"=>"Bernard", "last_name"=>"Portha", "scopus_author_id"=>"7005714764"}, {"first_name"=>"Jamileh", "last_name"=>"Movassat", "scopus_author_id"=>"6602405265"}], "year"=>2009, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"62749172470", "doi"=>"10.1371/journal.pone.0004734", "pui"=>"354344829", "pmid"=>"19266047", "scopus"=>"2-s2.0-62749172470", "issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)"}, "id"=>"6af0510f-fa78-3480-9d0f-6a793c9b19d4", "abstract"=>"BACKGROUND: Keratinocyte growth factor (KGF; palifermin) is a growth factor with a high degree of specificity for epithelial cells. KGF is an important effector of epithelial growth and tissue homeostasis in various organs including the pancreas. Here we investigated the intracellular signaling pathways involved in the mediation of pancreatic ductal cell proliferation and differentiation induced by exogenous KGF during beta-cell regeneration in diabetic rat.\\n\\nMETHODOLOGY AND RESULTS: In vitro and in vivo duct cell proliferation was measured by BrdU incorporation assay. The implication of MAPK-ERK1/2 in the mediation of KGF-induced cell proliferation was determined by inactivation of this pathway, using the pharmacological inhibitor or antisense morpholino-oligonucleotides against MEK1. In vivo KGF-induced duct cell differentiation was assessed by the immunolocalization of PDX1 and Glut2 in ductal cells and the implication of PI3K/AKT in this process was investigated. We showed that KGF exerted a potent mitogenic effect on ductal cells. Both in vitro and in vivo, its effect on cell proliferation was mediated through the activation of ERK1/2 as evidenced by the abolition of duct cell proliferation in the context of MEK/ERK inactivation. In vivo, KGF treatment triggered ductal cell differentiation as revealed by the expression of PDX1 and Glut2 in a subpopulation of ductal cells via a PI3K-dependent mechanism.\\n\\nCONCLUSION: Here we show that KGF promotes beta-cell regeneration by stimulating duct cell proliferation in vivo. Moreover, we demonstrated for the first time that KGF directly induces the expression of PDX1 in some ductal cells thus inducing beta-cell neogenesis. We further explored the molecular mechanisms involved in these processes and showed that the effects of KGF on duct cell proliferation are mediated by the MEK-ERK1/2 pathway, while the KGF-induced cell differentiation is mediated by the PI3K/AKT pathway. These findings might have important implications for the in vivo induction of duct-to-beta cell neogenesis in patients with beta-cell deficiency.", "link"=>"http://www.mendeley.com/research/mechanisms-kgf-mediated-signaling-pancreatic-duct-cell-proliferation-differentiation", "reader_count"=>17, "reader_count_by_academic_status"=>{"Student > Doctoral Student"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>6, "Student > Master"=>2, "Student > Bachelor"=>3, "Lecturer > Senior Lecturer"=>1, "Unspecified"=>1}, "reader_count_by_user_role"=>{"Student > Doctoral Student"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>6, "Student > Master"=>2, "Student > Bachelor"=>3, "Lecturer > Senior Lecturer"=>1, "Unspecified"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>4, "Medicine and Dentistry"=>1, "Agricultural and Biological Sciences"=>10, "Physics and Astronomy"=>1, "Unspecified"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>10}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Brazil"=>1}, "group_count"=>2}

Scopus | Further Information

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  • {"files"=>["https://ndownloader.figshare.com/files/906419"], "description"=>"<p>(A) Double staining for insulin (red cytosol) and PDX1 (brown nuclei) were performed on pancreatic sections of STZ, STZ/KGF, STZ/wortmannin and STZ/wortmannin/KGF rats (wortmannin was administrated at the dose of 0.75 mg/kg body weight). Differentiated beta cells express both insulin and PDX1 (blue arrow). A subset of ductal cells express PDX1 (red arrow) while the majority of ductal cells are PDX1 negative (green arrow) (actual magnification ×500). d = duct. (B) PDX1-positive / insulin-negative ductal cells were quantified after insulin/PDX1 staining on pancreatic sections of the 2-day-old STZ, STZ/KGF, STZ/wortmannin and STZ/wortmannin/KGF rats. Results are expressed as the percentage of PDX1-positive/insulin-negative cells over total ductal cells. Four rats were analyzed in each experimental group. * <i>p</i><0.05; ** <i>p</i><0.01. (C) Ductal cell proliferation was assessed by BrdU staining of pancreatic sections of the 2-day-old STZ, STZ/KGF, STZ/wortmannin and STZ/wortmannin/KGF rats and the results were expressed as the percentage of BrdU-positive ductal cells. Four rats were analyzed in each experimental group. * <i>p</i><0.05; ** <i>p</i><0.01.</p>", "links"=>[], "tags"=>["pathway", "wortmannin", "abolishes", "kgf-induced", "duct-to-beta", "differentiation", "kgf"], "article_id"=>576866, "categories"=>["Virology", "Infectious Diseases", "Cell Biology", "Physiology"], "users"=>["Benjamin Uzan", "Florence Figeac", "Bernard Portha", "Jamileh Movassat"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004734.g009", "stats"=>{"downloads"=>4, "page_views"=>43, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inactivation_of_PI3K_AKT_pathway_by_wortmannin_abolishes_KGF_induced_duct_to_beta_cell_differentiation_but_does_not_alter_the_effect_of_KGF_on_proliferation_/576866", "title"=>"Inactivation of PI3K/AKT pathway by wortmannin abolishes KGF-induced duct-to-beta cell differentiation but does not alter the effect of KGF on proliferation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 06:41:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/906287"], "description"=>"<p>PDX1-positive/insulin-negative ductal cells were quantified after insulin/PDX1 double staining of pancreatic sections of the 2-day-old STZ/Std, STZ/Std/KGF and STZ/MEK1-AS/KGF rats. Results are expressed as the percentage of PDX1-positive/insulin-negative ductal cells over total ductal cells. Four rats were analyzed in each experimental group. * <i>p</i><0.05.</p>", "links"=>[], "tags"=>["duct-", "to-", "beta", "differentiation"], "article_id"=>576739, "categories"=>["Virology", "Infectious Diseases", "Cell Biology", "Physiology"], "users"=>["Benjamin Uzan", "Florence Figeac", "Bernard Portha", "Jamileh Movassat"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004734.g007", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Activation_of_duct_to_beta_cell_differentiation_by_KGF_/576739", "title"=>"Activation of duct- to- beta cell differentiation by KGF.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 06:40:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/905993"], "description"=>"<p>Cell lysates were analyzed by western blot for cyclin D1 and cyclin D2 expression. (A) Cells were cultured in medium with 10% FBS. Basal levels of cyclin D2 were not detectable in Panc-1 cells as compared to its expression in insulinoma cell line, INS-1 used as control for the specificity of antibody. (B) Panc-1 cells were cultured in serum-free medium. Cells were then exposed or not to KGF or PD98059 alone, or to the combination of the two agents for 8 h. Cell lysates were analyzed by western blot for cyclin D1 expression. Results are expressed as mean values ±sem of three independent experiments. * <i>p</i><0.05.</p>", "links"=>[], "tags"=>["d-type", "cyclins"], "article_id"=>576454, "categories"=>["Virology", "Infectious Diseases", "Cell Biology", "Physiology"], "users"=>["Benjamin Uzan", "Florence Figeac", "Bernard Portha", "Jamileh Movassat"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004734.g004", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Induction_of_D_type_cyclins_by_KGF_/576454", "title"=>"Induction of D-type cyclins by KGF.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 06:39:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/905910"], "description"=>"<p>(A) Panc-1 cells were cultured in serum-free medium and treated for 24 h with MEK1 antisense morpholino-oligonucleotides (MEK1-AS, 10 nmol/ml) or standard morpholino-oligonucleotides (Std, 10 nmol/ml). Cell lysates were analyzed by western blot using specific antibody against MEK1. Representative blots and MEK1 protein quantification are shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0004734#pone-0004734-g003\" target=\"_blank\">Figure 3A</a>. Results are expressed as mean values ±sem of 4 independent experiments. * <i>p</i><0.05. (B) Panc-1 cells were treated with MEK1-AS or Std during 24 h, then stimulated with KGF for 5 minutes before the end of the experiments. Cell lysates were analyzed by western blot for P-ERK1/2 and total-ERK1/2 expression. (C) Panc-1 cells were cultured in serum-free medium and pre-treated with MEK1-AS during 24 h prior the addition of KGF or 10% FBS. BrdU labelling index of Panc-1 cells was evaluated and expressed as the percentage of BrdU-positive Panc-1 cells. Results are presented as mean values ±sem of three independent experiments. * <i>p</i><0.05.</p>", "links"=>[], "tags"=>["pathway", "antisense", "morpholino-oligonucleotides", "abolishes", "kgf-induced", "proliferation", "panc-1"], "article_id"=>576363, "categories"=>["Virology", "Infectious Diseases", "Cell Biology", "Physiology"], "users"=>["Benjamin Uzan", "Florence Figeac", "Bernard Portha", "Jamileh Movassat"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004734.g003", "stats"=>{"downloads"=>5, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inactivation_of_ERK1_2_pathway_by_antisense_morpholino_oligonucleotides_abolishes_KGF_induced_proliferation_of_Panc_1_cells_/576363", "title"=>"Inactivation of ERK1/2 pathway by antisense morpholino-oligonucleotides abolishes KGF-induced proliferation of Panc-1 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 06:38:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/906168"], "description"=>"<p>(A) Rats from STZ/Std and STZ/MEK1-AS groups were sacrificed at day 2 post natal. Pancreases were removed and pancreatic protein extracts were analyzed by western blot using a specific MEK1 antibody. Representative blots and MEK1 protein quantification are shown in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0004734#pone-0004734-g006\" target=\"_blank\">Figure 6A</a>. Results are expressed as mean values ±sem. Four rats were analyzed in each experimental group. * <i>p</i><0.05. (B) BrdU (brown nuclei) and CK20 staining (red cytosol) of pancreatic sections from 2-day-old STZ/Std/KGF and STZ/MEK1-AS/KGF newborns (actual magnification ×500). (C) Ductal cell proliferation was assessed by BrdU staining of pancreatic sections of STZ/Std, STZ/MEK1-AS, STZ/Std/KGF and STZ/MEK1-AS/KGF groups. BrdU labelling index of ductal cells in all experimental groups was evaluated in 2-day-old pups and the results were expressed as the percentage of BrdU-positive ductal cells. Three to five rats were analyzed in each experimental group. ** <i>p</i><0.01.</p>", "links"=>[], "tags"=>["pathway", "mek1-as", "abolishes", "kgf-induced", "duct"], "article_id"=>576621, "categories"=>["Virology", "Infectious Diseases", "Cell Biology", "Physiology"], "users"=>["Benjamin Uzan", "Florence Figeac", "Bernard Portha", "Jamileh Movassat"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004734.g006", "stats"=>{"downloads"=>2, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inactivation_of_ERK1_2_pathway_by_MEK1_AS_abolishes_KGF_induced_duct_cell_proliferation_/576621", "title"=>"Inactivation of ERK1/2 pathway by MEK1-AS abolishes KGF-induced duct cell proliferation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 06:40:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/906075"], "description"=>"<p>Two-day-old STZ diabetic rats were administrated with 3 mg/kg KGF, 20 minutes before the sacrifice. Pancreases were removed and pancreatic protein extracts were analyzed by western blot for the expression of P-ERK1/2 and total-ERK1/2 proteins. Four and five rats were analyzed in the STZ/saline and STZ/KGF group respectively.</p>", "links"=>[], "tags"=>["pathway", "kgf", "pancreas", "neonatal", "diabetic"], "article_id"=>576530, "categories"=>["Virology", "Infectious Diseases", "Cell Biology", "Physiology"], "users"=>["Benjamin Uzan", "Florence Figeac", "Bernard Portha", "Jamileh Movassat"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004734.g005", "stats"=>{"downloads"=>5, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Activation_of_ERK1_2_pathway_by_KGF_in_the_pancreas_of_neonatal_diabetic_rats_/576530", "title"=>"Activation of ERK1/2 pathway by KGF in the pancreas of neonatal diabetic rats.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 06:39:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/906336"], "description"=>"<p>Glut 2-positive/insulin-negative cells were quantified after insulin/Glut 2 double staining of pancreatic sections of the 4-day-old STZ/saline and STZ/KGF groups. Results are expressed as the percentage of Glut 2-positive/insulin-negative ductal cells over total ductal cells. Four rats were analyzed in each experimental group. * <i>p</i><0.05.</p>", "links"=>[], "tags"=>["duct-", "to-", "beta", "differentiation"], "article_id"=>576791, "categories"=>["Virology", "Infectious Diseases", "Cell Biology", "Physiology"], "users"=>["Benjamin Uzan", "Florence Figeac", "Bernard Portha", "Jamileh Movassat"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004734.g008", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Activation_of_duct_to_beta_cell_differentiation_by_KGF_/576791", "title"=>"Activation of duct- to- beta cell differentiation by KGF.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 06:41:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/905729"], "description"=>"<p>(A) Panc-1 cells were cultured in serum-free medium with or without KGF (30 ng/ml) or with 10% FBS for 24 h. BrdU was added to the culture media 1 h before the end of the experiments. Results are expressed as mean values ±sem of three independent experiments. ** <i>p</i><0.01. (B) Phosphorylation of ERK1/2 was evaluated by western blot analysis in cell extracts from Panc-1 cells stimulated for 5, 20 and 60 minutes with KGF, or with 10% FBS for 20 minutes. Western blot analysis of total-ERK1/2 protein was used as control.</p>", "links"=>[], "tags"=>["stimulates", "proliferation", "activates"], "article_id"=>576184, "categories"=>["Virology", "Infectious Diseases", "Cell Biology", "Physiology"], "users"=>["Benjamin Uzan", "Florence Figeac", "Bernard Portha", "Jamileh Movassat"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004734.g001", "stats"=>{"downloads"=>2, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_KGF_stimulates_cell_proliferation_and_activates_ERK1_2_pathway_/576184", "title"=>"KGF stimulates cell proliferation and activates ERK1/2 pathway.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 06:37:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/905800"], "description"=>"<p>(A) Panc-1 cells were pre-incubated for 1 h with 20 µM, 10 µM and 1 µM of PD98059, an inhibitor of MEK1. Cells were then treated for 5 minutes with 30 ng/ml KGF. Cell lysates were analyzed by western blot using specific antibodies against P-ERK1/2 and total-ERK1/2. (B) Panc-1 cells were cultured in serum-free medium. Cells were then exposed or not to KGF or PD98059 alone, or to the combination of the two agents for 24 h. Cell proliferation was assessed by BrdU staining (brown nuclei). Red arrows show BrdU-positive Panc-1 cells and blue arrows show BrdU-negative Panc-1 cells (actual magnification ×250). (C) Panc-1 cells were treated or not with 20 µM PD98059, 1 h prior to the 24 h incubation with KGF or 10% FBS. BrdU labelling index of Panc-1 cells was evaluated and expressed as the percentage of BrdU-positive Panc-1 cells. Results are presented as mean values ±sem of three independent experiments. ** <i>p</i><0.01.</p>", "links"=>[], "tags"=>["pathway", "pharmacological", "inhibitor", "abolishes", "kgf-induced", "panc-1"], "article_id"=>576251, "categories"=>["Virology", "Infectious Diseases", "Cell Biology", "Physiology"], "users"=>["Benjamin Uzan", "Florence Figeac", "Bernard Portha", "Jamileh Movassat"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0004734.g002", "stats"=>{"downloads"=>2, "page_views"=>27, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inactivation_of_ERK1_2_pathway_by_pharmacological_inhibitor_abolishes_KGF_induced_Panc_1_cell_proliferation_/576251", "title"=>"Inactivation of ERK1/2 pathway by pharmacological inhibitor abolishes KGF-induced Panc-1 cell proliferation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-21 06:38:12"}

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  • {"unique-ip"=>"8", "full-text"=>"9", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"8", "full-text"=>"9", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"7", "full-text"=>"7", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"13", "full-text"=>"13", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}

Relative Metric

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