Spelling suggestions: "subject:"smad2"" "subject:"smad3""
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A novel Smad4 model of hereditary hemorrhagic telangiectasia links Angiopoietin-Tie signaling to arteriovenous malformation developmentJanuary 2019 (has links)
archives@tulane.edu / 1 / Angela Crist
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Identification of Germline Alterations in the Mad-homology 2 (MH2) Domain of SMAD3 and SMAD4 In Breast Cancer SusceptibilityTram, Eric 03 December 2012 (has links)
A feature of neoplastic cells is that mutations in the key intermediates of TGF-β signaling contribute to the loss of sensitivity to its anti-tumor effects. The role of SMAD3 and SMAD4 germline mutations in breast cancer predisposition is currently unclear. To address this, mutation analysis of the Mad-Homology 2 domains in 408 breast cancer cases and 710 controls recruited by the Breast Cancer Family Registry (BCFR) was performed using Denaturing High-Pressure Liquid Chromatography. This study identified 23 distinct intronic variants, and three coding variants c.1214T>C, c.1478G>A, and c.1701A>G in SMAD4. No aberrant splicing was observed, but qPCR analysis and tissue expression data showed significantly elevated SMAD3 expression relative to controls (p<0.05). For SMAD4, c.1478G>A from a familial breast cancer case showed a 5-fold expression change. Taken together, inactivating alterations are not driving tumorigenesis. Rather, aberrant germline expression provides novel insight into SMAD3 and SMAD4’s roles in breast cancer predisposition.
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Identification of Germline Alterations in the Mad-homology 2 (MH2) Domain of SMAD3 and SMAD4 In Breast Cancer SusceptibilityTram, Eric 03 December 2012 (has links)
A feature of neoplastic cells is that mutations in the key intermediates of TGF-β signaling contribute to the loss of sensitivity to its anti-tumor effects. The role of SMAD3 and SMAD4 germline mutations in breast cancer predisposition is currently unclear. To address this, mutation analysis of the Mad-Homology 2 domains in 408 breast cancer cases and 710 controls recruited by the Breast Cancer Family Registry (BCFR) was performed using Denaturing High-Pressure Liquid Chromatography. This study identified 23 distinct intronic variants, and three coding variants c.1214T>C, c.1478G>A, and c.1701A>G in SMAD4. No aberrant splicing was observed, but qPCR analysis and tissue expression data showed significantly elevated SMAD3 expression relative to controls (p<0.05). For SMAD4, c.1478G>A from a familial breast cancer case showed a 5-fold expression change. Taken together, inactivating alterations are not driving tumorigenesis. Rather, aberrant germline expression provides novel insight into SMAD3 and SMAD4’s roles in breast cancer predisposition.
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Tranilast Inhibits TGF-β1-induced Epithelial-mesenchymal Transition and Invasion/Metastasis via the Suppression of Smad4 in Human Lung Cancer Cell Lines / ヒト非小細胞肺癌細胞株において、トラニラストはTGF-β1で誘導された上皮-間葉転換と浸潤/転移を、Smad4を抑制することにより回復させるTakahashi, Koji 23 March 2022 (has links)
京都大学 / 新制・課程博士 / 博士(医学) / 甲第23768号 / 医博第4814号 / 新制||医||1056(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 松田 道行, 教授 渡邊 直樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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In Vitro Modeling of Pancreatic Duct Cell CarcinogenesisLeung, Lisa 20 June 2014 (has links)
Pancreatic adenocarcinoma (PDAC) putatively arises from the pancreatic duct, thus usage of the normal human pancreatic duct epithelial (HPDE) cell line is an ideal model to examine the successive accumulation of genetic alterations involved in carcinogenesis. KRAS mutations have been reported in 90% of PDACs. Oncogenic KRAS elicits activation of downstream pathways involved in survival, motility, and cell cycle progression. KRASG12V introduction in the HPDE cell line upregulates Lipocalin-2 (LCN2) expression. LCN2 has been identified in numerous carcinomas and is associated with survival, tumorigenicity, and invasion. In this work, LCN2 was found to be commonly expressed in high grade pancreatic duct neoplastic precursor lesions and PDAC illustrating its potential as a biomarker. Moreover, in vitro and in vivo studies demonstrate that high LCN2 expression promotes gemcitabine resistance, MMP-9 activity, angiogenesis, and tumorigenicity.
Loss of Smad4 function is found in 55% of PDAC cases. Smad4 is a critical component in the TGF-β signaling which mediates the transcription of genes involved in processes such as cell cycle arrest, apoptosis, and invasion. This work examined the consequences of KRASG12V expression and Smad4 loss in the HPDE model. Cellular invasion was promoted by KRASG12V expression or knocking down Smad4 by 80% in the HPDE model. A TGF-β resistant HPDE cell line, TβR, was shown to lack Smad4 expression due to deletion, promoter methylation, and nonsense mutation. KRASG12V expression in the TβR model (TβR KRAS) promoted neoplastic transformation and tumour formation in immunodeficient mice with complete penetrance. Smad4 expression in the TβR KRAS cell line reinstated TGF-β signaling, delayed tumour formation, and decreased metastatic spread. This study provides evidence that Smad4 acts as a restriction point in the transformation of HPDE cells. Overall, this work examines the contribution of genes involved in transformation, and identifies a potential therapeutic and diagnostic biomarker in PDAC.
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BMP-SMAD1/4 upregulates HNF4α in a subset of heterogeneous mouse pancreatic cancer cells while under metabolic stressHeung, Man Yeung January 2013 (has links)
It is not known whether pancreatic cancers evolve from a single or multiple cells, or from a particular pancreatic lineage. However, in the Pdx1-Cre; LSL-KrasG12D; LSLTp53R172H mouse model of pancreatic cancer, all pancreatic lineages are susceptible to express mutant KRas and p53. Hence, such mouse model implies a scenario of maximal heterogeneity of cancer cell origins. On this basis, I isolated seven subclones of heterogeneous mouse pancreatic cancer cells from a single tumour; each of them had a distinct morphology and gene expression profile. Notably, they possessed different intrinsic phospho-SMADs downstream of the TGFβ receptor (phospho-SMAD2/3) or the BMP receptor (Phospho-SMAD1/5/8). I discovered that SMAD4, a co-SMAD which is frequently found to be lost in pancreatic caner tissues, upregulated HNF4α via the classical BMP-SMAD1 pathway, when cells were experiencing metabolic stress upon deprivation of serum, or in the presence of excess thymidine. Under serum starvation at a hypoglycemic-like glucose concentration, the HNF4α-expressing sub-clones appeared to be more able to sustain an unstressed morphology than other non-HNF4α-expressing sub-clones. Immunohistochemical staining on pancreatic cancer sections revealed nuclear co-localization of SMAD4 and HNF4α in human (half of the cases) and in mouse samples. As a secondary project conducted during characterization of cells, I also found that three of the subclones more robustly proliferated under anchorage independent conditions, and they relied on the MEK-ERK pathway and the canonical Wnt pathway, to a different degree. Both studies demonstrate for the first time in primary cell culture that pancreatic cancer cells within a tumour could be highly heterogeneous in terms of both morphology and signaling pathways.
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In Vitro Modeling of Pancreatic Duct Cell CarcinogenesisLeung, Lisa 20 June 2014 (has links)
Pancreatic adenocarcinoma (PDAC) putatively arises from the pancreatic duct, thus usage of the normal human pancreatic duct epithelial (HPDE) cell line is an ideal model to examine the successive accumulation of genetic alterations involved in carcinogenesis. KRAS mutations have been reported in 90% of PDACs. Oncogenic KRAS elicits activation of downstream pathways involved in survival, motility, and cell cycle progression. KRASG12V introduction in the HPDE cell line upregulates Lipocalin-2 (LCN2) expression. LCN2 has been identified in numerous carcinomas and is associated with survival, tumorigenicity, and invasion. In this work, LCN2 was found to be commonly expressed in high grade pancreatic duct neoplastic precursor lesions and PDAC illustrating its potential as a biomarker. Moreover, in vitro and in vivo studies demonstrate that high LCN2 expression promotes gemcitabine resistance, MMP-9 activity, angiogenesis, and tumorigenicity.
Loss of Smad4 function is found in 55% of PDAC cases. Smad4 is a critical component in the TGF-β signaling which mediates the transcription of genes involved in processes such as cell cycle arrest, apoptosis, and invasion. This work examined the consequences of KRASG12V expression and Smad4 loss in the HPDE model. Cellular invasion was promoted by KRASG12V expression or knocking down Smad4 by 80% in the HPDE model. A TGF-β resistant HPDE cell line, TβR, was shown to lack Smad4 expression due to deletion, promoter methylation, and nonsense mutation. KRASG12V expression in the TβR model (TβR KRAS) promoted neoplastic transformation and tumour formation in immunodeficient mice with complete penetrance. Smad4 expression in the TβR KRAS cell line reinstated TGF-β signaling, delayed tumour formation, and decreased metastatic spread. This study provides evidence that Smad4 acts as a restriction point in the transformation of HPDE cells. Overall, this work examines the contribution of genes involved in transformation, and identifies a potential therapeutic and diagnostic biomarker in PDAC.
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Loss of SMAD4 Promotes Colorectal Cancer Progression by Recruiting Tumor-Associated Neutrophils via the CXCL1/8-CXCR2 Axis / 大腸癌のSMAD4欠損によりケモカインCXCL1/8が分泌され、CXCR2陽性腫瘍関連好中球が集積し、腫瘍の増殖に関与するOgawa, Ryotaro 25 November 2019 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22120号 / 医博第4533号 / 新制||医||1039(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 妹尾 浩, 教授 竹内 理, 教授 濵﨑 洋子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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Loss of Smad4 From Colorectal Cancer Cells Promotes CCL15 Expression to Recruit CCR1+ Myeloid Cells and Facilitate Liver Metastasis / 大腸癌細胞でのSmad4欠損によりCCL15の発現が誘導され、CCR1+骨髄由来細胞が集積し肝転移が促進されるItatani, Yoshiro 24 March 2014 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18127号 / 医博第3847号 / 新制||医||1001(附属図書館) / 30985 / 京都大学大学院医学研究科医学専攻 / (主査)教授 千葉 勉, 教授 松田 道行, 教授 野田 亮 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM
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Loss of SMAD4 Promotes Lung Metastasis of Colorectal Cancer by Accumulation of CCR1+ Tumor-associated Neutrophils through CCL15-CCR1 Axis / 大腸癌のSMAD4欠損によりケモカインCCL15が分泌され、腫瘍周囲にCCR1陽性腫瘍関連好中球(TAN)が集積し、肺転移が促進するYamamoto, Takamasa 23 March 2017 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20229号 / 医博第4188号 / 新制||医||1019(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 武藤 学, 教授 原田 浩, 教授 山田 泰広 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM
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