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J M Bailey, A M Hendley, K J Lafaro, M A Pruski, N C Jones, J Alsina, M Younes, A Maitra, F McAllister, C A Iacobuzio-Donahue, S D Leach
Pancreatic cancer is one of the most lethal malignancies, with virtually all patients eventually succumbing to their disease. Mutations in p53 have been documented in >50% of pancreatic cancers. Owing to the high incidence of p53 mutations in PanIN 3 lesions and pancreatic tumors, we interrogated the comparative ability of adult pancreatic acinar and ductal cells to respond to oncogenic Kras and mutant Tp53(R172H) using Hnf1b:CreER(T2) and Mist1:CreER(T2) mice. These studies involved co-activation of a membrane-tethered GFP lineage label, allowing for direct visualization and isolation of cells undergoing Kras and mutant p53 activation...
August 11, 2016: Oncogene
Richard W Naylor, Alan J Davidson
The nephron is the functional unit that executes the homeostatic roles of the kidney in vertebrates. Critical to this function is the physical arrangement of the glomerular blood filter attached to a tubular epithelium that is subdivided into specialized proximal and distal segments. During embryogenesis, nephron progenitors undergo a mesenchymal-epithelial transition (MET) and adopt different segment-specific cell fates along the proximo-distal axis of the nephron. The molecular basis of how these segments arise remains largely unknown...
April 2014: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Kameswaran Surendran, Meron Selassie, Helen Liapis, Hannah Krigman, Raphael Kopan
The formation of proximal nephron segments requires canonical Notch2 signaling, but other functions of Notch signaling during renal development are incompletely understood. Here, we report that proximal tubules forming with reduced Notch signaling, resulting from delayed conditional inactivation of Notch1 and/or Notch2, are prone to cyst formation and tubular epithelial stratification. Conditional inactivation of the DNA binding factor RBP-J, which mediates Notch signaling, also resulted in multiple congenital cysts arising from the proximal tubule...
May 2010: Journal of the American Society of Nephrology: JASN
Laurence Heidet, Stéphane Decramer, Audrey Pawtowski, Vincent Morinière, Flavio Bandin, Bertrand Knebelmann, Anne-Sophie Lebre, Stanislas Faguer, Vincent Guigonis, Corinne Antignac, Rémi Salomon
BACKGROUND AND OBJECTIVES: Hepatocyte nuclear factor 1beta (HNF1beta) is a transcription factor that is critical for the development of kidney and pancreas. In humans, mutations in HNF1B lead to congenital anomalies of the kidney and urinary tract, pancreas atrophy, and maturity-onset diabetes of the young type 5 and genital malformations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We report HNF1B screening in a cohort of 377 unrelated cases with various kidney phenotypes (hyperechogenic kidneys with size not more than +3 SD, multicystic kidney disease, renal agenesis, renal hypoplasia, cystic dysplasia, or hyperuricemic tubulointerstitial nephropathy not associated with UMOD mutation)...
June 2010: Clinical Journal of the American Society of Nephrology: CJASN
J-P Le Berre, C Bellanné-Chantelot, L Bordier, C Garcia, O Dupuy, H Mayaudon, B Bauduceau
A 55-year-old woman presented with a recent diabetes mellitus associated with pancreatic and renal malformations. This atypical diabetes raised the possibility of maturity onset diabetes of the young (MODY) and a genetic research was performed. These malformations led to MODY5 diagnosis that was confirmed by the presence of HNF1beta gene mutation.
June 2010: La Revue de Médecine Interne
Makiko Nakayama, Kandai Nozu, Yuki Goto, Koichi Kamei, Shuichi Ito, Hidenori Sato, Mitsuru Emi, Koichi Nakanishi, Shigeru Tsuchiya, Kazumoto Iijima
Hepatocyte nuclear factor 1beta (HNF1beta) abnormalities have been recognized to cause congenital anomalies of the kidney and urinary tract (CAKUT), predominantly affecting bilateral renal malformations. To further understand the spectrum of HNF1beta related phenotypes, we performed HNF1B gene mutation and deletion analyses in Japanese patients with renal hypodysplasia (n = 31), unilateral multicystic dysplastic kidney (MCDK; n = 14) and others (n = 5). We identified HNF1B alterations in 5 out of 50 patients (10%)...
June 2010: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Myriam Solar, Carina Cardalda, Isabelle Houbracken, Mercè Martín, Miguel Angel Maestro, Nele De Medts, Xiaobo Xu, Vanessa Grau, Harry Heimberg, Luc Bouwens, Jorge Ferrer
A longstanding unsettled question is whether pancreatic beta cells originate from exocrine duct cells. We have now used genetic labeling to fate map embryonic and adult pancreatic duct cells. We show that Hnf1beta+ cells of the trunk compartment of the early branching pancreas are precursors of acinar, duct, and endocrine lineages. Hnf1beta+ cells subsequent form the embryonic duct epithelium, which gives rise to both ductal and endocrine lineages, but not to acinar cells. By the end of gestation, the fate of Hnf1beta+ duct cells is further restrained...
December 2009: Developmental Cell
Ludmilla Lokmane, Claire Heliot, Pilar Garcia-Villalba, Mélanie Fabre, Silvia Cereghini
Mouse metanephric kidney development begins with the induction of the ureteric bud (UB) from the caudal portion of the Wolffian duct by metanephric mesenchymal signals. While the UB undergoes branching morphogenesis to generate the entire urinary collecting system and the ureter, factors secreted by the UB tips induce surrounding mesenchymal cells to convert into epithelia and form the nephrons, the functional units of the kidney. Epithelial branching morphogenesis and nephrogenesis are therefore tightly orchestrated; defects in either of these processes lead to severe kidney phenotypes ranging from hypoplasia to complete aplasia...
January 2010: Development
Methichit Chayosumrit, Bernard Tuch, Kuldip Sidhu
Human embryonic stem cells (hESCs) are potential renewable sources of cells in replacement therapies for many diseases including type 1 diabetes. We have established a three dimensional (3D) model to culture and differentiate hESCs that are encapsulated in calcium alginate microcapsules. This system promotes cellular interactions that are essential for both maintaining pluripotency and differentiation. This 3D model also provides opportunity to separate out hESCs from fibroblasts used as feeder layer during culture...
January 2010: Biomaterials
Peng Liu, Ashwani Khurana, Ramandeep Rattan, Xiaoping He, Steve Kalloger, Sean Dowdy, Blake Gilks, Viji Shridhar
We recently identified HSulf-1 as a down-regulated gene in ovarian carcinomas. Our previous analysis indicated that HSulf-1 inactivation in ovarian cancers is partly mediated by loss of heterozygosity and epigenetic silencing. Here, we show that variant hepatic nuclear factor 1 (vHNF1), encoded by transcription factor 2 gene (TCF2, HNF1beta), negatively regulates HSulf-1 expression in ovarian cancer. Immunoblot assay revealed that vHNF1 is highly expressed in HSulf-1-deficient OV207, SKOV3, and TOV-21G cell lines but not in HSulf-1-expressing OSE, OV167, and OV202 cells...
June 1, 2009: Cancer Research
Naoki Tanimizu, Atsushi Miyajima, Keith E Mostov
Bile ducts are hepatic tubular structures that are lined by cholangiocytes, a type of liver epithelial cell. Cholangiocytes first form a single layer of cells, termed the ductal plate, surrounding the portal vein, which eventually remodels into the branching tubular network of bile ducts. The process of bile duct morphogenesis is not yet clear: a conventional model where cholangiocytes proliferate to duplicate a single layer of the ductal plate before lumen formation seems inconsistent with the observation that proliferation is dramatically reduced when hepatoblasts, liver progenitor cells, differentiate into cholangiocytes...
May 2009: Molecular Biology of the Cell
Joan-Marc Servitja, Miguel Pignatelli, Miguel Angel Maestro, Carina Cardalda, Sylvia F Boj, Juanjo Lozano, Enrique Blanco, Amàlia Lafuente, Mark I McCarthy, Lauro Sumoy, Roderic Guigó, Jorge Ferrer
Heterozygous HNF1A mutations cause pancreatic-islet beta-cell dysfunction and monogenic diabetes (MODY3). Hnf1alpha is known to regulate numerous hepatic genes, yet knowledge of its function in pancreatic islets is more limited. We now show that Hnf1a deficiency in mice leads to highly tissue-specific changes in the expression of genes involved in key functions of both islets and liver. To gain insights into the mechanisms of tissue-specific Hnf1alpha regulation, we integrated expression studies of Hnf1a-deficient mice with identification of direct Hnf1alpha targets...
June 2009: Molecular and Cellular Biology
Congrong Wang, Cheng Hu, Rong Zhang, Yuqian Bao, Xiaojing Ma, Jingyi Lu, Wen Qin, Xinyu Shao, Junxi Lu, Jing Xu, Huijuan Lu, Kunsan Xiang, Weiping Jia
OBJECTIVE: Hepatocyte nuclear factor 1beta (HNF1beta) is a transcription factor that is critical for pancreatic cell formation and glucose homeostasis. Previous studies have reported that common variants of HNF1beta were associated with type 2 diabetes in Caucasians and West Africans. However, analysis in the subjects from the Botnia study and Malmö Preventive Project produced conflicting results, and the role for HNF1beta in type 2 diabetes susceptibility remains unclear. We therefore investigated common variants across the HNF1beta gene in a Chinese population...
April 2009: Diabetes
Sook Wah Yee, James E Shima, Stephanie Hesselson, Loan Nguyen, Sarah De Val, Rachel J Lafond, Michiko Kawamoto, Susan J Johns, Doug Stryke, Pui-Yan Kwok, Thomas E Ferrin, Brian L Black, David Gurwitz, Nadav Ahituv, Kathleen M Giacomini
The human concentrative nucleoside transporter 2 (CNT2) plays an important role in the absorption, disposition, and biological effects of endogenous nucleosides and nucleoside analog drugs. We identified genetic variation in the basal promoter region of CNT2 and characterized the function of the variants. We screened DNA from an ethnically diverse population and identified five basal promoter variants in CNT2. Three major haplotypes in the CNT2 basal promoter region were identified and were found at different allele frequencies in various ethnic groups...
March 2009: Journal of Pharmacology and Experimental Therapeutics
Ethan Yixun Xu, Ally Perlina, Heather Vu, Sean P Troth, Richard J Brennan, Amy G Aslamkhan, Qiuwei Xu
In this study, approximately 40 endogenous metabolites were identified and quantified by (1)H NMR in urine samples from male rats dosed with two proximal tubule toxicants, cisplatin and gentamicin. The excreted amount of a majority of those metabolites in urine was found to be dose-dependent and exhibited a strong correlation with histopathology scores of overall proximal tubule damage. MetaCore pathway analysis software (GeneGo Inc.) was employed to identify nephrotoxicant-associated biochemical changes via an integrated quantitative analysis of both urine metabolomic and kidney transcriptomic profiles...
August 2008: Chemical Research in Toxicology
Evelyne Fischer, Marco Pontoglio
The genetic program controlled by transcription factors can be modulated by multiple mechanisms. Binding of coactivators or corepressors, for example, can modulate the transcription of target genes. Dudziak and colleagues identified novel HNF1beta-interacting proteins that, when overexpressed, affect nephrogenesis. These results could improve our understanding of the way HNF1beta controls kidney development.
July 2008: Kidney International
Pallavi B Limaye, Gabriela Alarcón, Andrew L Walls, Michael A Nalesnik, George K Michalopoulos, Anthony J Demetris, Erin R Ochoa
Transcription factors are major determinants of cell-specific gene expression in all cell types. Studies in rodent liver have shown that alterations in transcription factor expression determine lineage specification during fetal liver development and signify transdifferentiation of cells of the biliary compartment into 'oval' cells and eventually hepatocytes in adult liver. We examined the cellular localization of hepatocyte- or BEC-associated transcription factors in human fetal and adult liver and in diseases in which transdifferentiation between hepatocytes and biliary cells may play a role...
August 2008: Laboratory Investigation; a Journal of Technical Methods and Pathology
Louise Chappell, Shaun Gorman, Fiona Campbell, Sian Ellard, Gillian Rice, Angus Dobbie, Yanick Crow
We report a patient born to consanguineous parents as a further example of a recently described phenotype comprising neonatal diabetes, intestinal atresias and gall bladder agenesis. Other reports have described cases with overlapping patterns including malrotation, biliary atresia and pancreatic hypoplasia (e.g. as described by Martínez-Frías). We propose that these cases may represent variations of the same syndrome. It is likely that this disorder is inherited as an autosomal recessive trait. Our case is the first to have neonatal diabetes without a demonstrable structural pancreatic abnormality, showing that a deficit in pancreatic function is involved...
July 1, 2008: American Journal of Medical Genetics. Part A
Karin Dudziak, Nima Mottalebi, Sabine Senkel, Emma L Edghill, Stefan Rosengarten, Magdalena Roose, Coralie Bingham, Sian Ellard, Gerhart U Ryffel
Heterozygous mutations of the tissue-specific transcription factor hepatocyte nuclear factor (HNF)1beta, cause maturity onset diabetes of the young (MODY5) and kidney anomalies including agenesis, hypoplasia, dysplasia and cysts. Because of these renal anomalies, HNF1beta is classified as a CAKUT (congenital anomalies of the kidney and urinary tract) gene. We searched for human fetal kidney proteins interacting with the N-terminal region of HNF1beta using a bacterial two-hybrid system and identified five novel proteins along with the known partner DCoH...
July 2008: Kidney International
Gaelle del Castillo, Alberto Alvarez-Barrientos, Irene Carmona-Cuenca, Margarita Fernández, Aránzazu Sánchez, Isabel Fabregat
The "in vitro" establishment of a physiological model of bipotential liver progenitors would be useful for analyzing the molecular mechanisms involved in regulating growth and differentiation, as well as studying their potential role/s in liver physiology and pathology. The transforming growth factor-beta (TGF-beta) induces de-differentiation of fetal rat hepatocytes (FH), concomitant with changes in morphology. The aim of this work was to isolate and characterize this population of TGF-beta-treated fetal hepatocytes (TbetaT-FH) and test whether they can behave as liver progenitors...
June 2008: Journal of Cellular Physiology
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