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Robert Neff, Craig M Rush, Blair Smith, Floor J Backes, David E Cohn, Paul J Goodfellow
FOXA2, a member of the forkhead family of DNA-binding proteins, is frequently mutated in uterine cancers. Most of the mutations observed in uterine cancers are frameshifts and stops. FOXA2 is considered to be a driver gene in uterine cancers, functioning as a haploinsufficient tumor suppressor. The functional consequences of FOXA2 mutations, however, have not yet been determined. We evaluated the effects that frameshift mutations as well as a recurrent missense mutation have on FOXA2 transcriptional activity...
August 9, 2018: International Journal of Cancer. Journal International du Cancer
Sonya Galcheva, Sara Al-Khawaga, Khalid Hussain
Hyperinsulinaemic hypoglycaemia (HH) is a heterogeneous condition with dysregulated insulin secretion which persists in the presence of low blood glucose levels. It is the most common cause of severe and persistent hypoglycaemia in neonates and children. Recent advances in genetics have linked congenital HH to mutations in 14 different genes that play a key role in regulating insulin secretion (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, UCP2, HNF4A, HNF1A, HK1, PGM1, PPM2, CACNA1D, FOXA2). Histologically, congenital HH can be divided into 3 types: diffuse, focal and atypical...
August 2018: Best Practice & Research. Clinical Endocrinology & Metabolism
Vasumathi Kameswaran, Maria Golson, Mireia Ramos-Rodríguez, Kristy Ou, Yue J Wang, Jia Zhang, Lorenzo Pasquali, Klaus H Kaestner
Type 2 diabetes mellitus (T2DM) is characterized by the inability of the insulin-producing β-cells to overcome insulin resistance. We previously identified an imprinted region on chromosome 14, the DLK1 - MEG3 locus, as being down-regulated in human T2D islets. Here, using targeted epigenetic modifiers, we prove that increased methylation at the promoter of Meg3 in mouse βTC6 β-cells results in decreased transcription of the maternal transcripts associated with this locus. As a result, the sensitivity of β-cells to cytokine-mediated oxidative stress was increased...
July 3, 2018: Diabetes
Chenyi Ye, Mo Chen, Erman Chen, Weixu Li, Shengdong Wang, Qianhai Ding, Cong Wang, Chenhe Zhou, Lan Tang, Weiduo Hou, Kai Hang, Rongxin He, Zhijun Pan, Wei Zhang
Forkhead box protein A2 (FOXA2) is a core transcription factor that controls cell differentiation and may have an important role in bone metabolism. However, the role of FOXA2 during osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) remains largely unknown. In this study, decreased expression of FOXA2 was observed during osteogenic differentiation of rat BMSCs (rBMSCs). FOXA2 knockdown significantly increased osteoblast-specific gene expression, the number of mineral deposits and alkaline phosphatase activity, whereas FOXA2 overexpression inhibited osteogenesis-specific activities...
August 6, 2018: Cell Death & Disease
Ching-In Lau, Diana C Yánez, Anisha Solanki, Eleftheria Papaioannou, José Ignacio Saldaña, Tessa Crompton
The Foxa1 and Foxa2 transcription factors are essential for mouse development. Here we show that they are expressed in thymic epithelial cells (TEC) where they regulate TEC development and function, with important consequences for T-cell development. TEC are essential for T-cell differentiation, lineage decisions and repertoire selection. Conditional deletion of Foxa1 and Foxa2 from murine TEC led to a smaller thymus with a greater proportion of TEC and a greater ratio of medullary to cortical TEC. Cell-surface MHCI expression was increased on cortical TEC in the conditional Foxa1Foxa2 knockout thymus, and MHCII expression was reduced on both cortical and medullary TEC populations...
July 27, 2018: Journal of Autoimmunity
Masaki Shoji, Hiroki Minato, Soichiro Ogaki, Masahide Seki, Yutaka Suzuki, Shoen Kume, Takashi Kuzuhara
The crosstalk between cells is important for differentiation of cells. Murine-derived feeder cells, SNL76/7 feeder cells (SNLs) or mouse primary embryonic fibroblast feeder cells (MEFs) are widely used for culturing undifferentiated human induced pluripotent stem cells (hiPSCs). It is still unclear whether different culture conditions affect the induction efficiency of definitive endoderm (DE) differentiation from hiPSCs. Here we show that the efficiency of DE differentiation from hiPSCs cultured on MEFs was higher than that of hiPSCs cultured on SNLs...
2018: PloS One
Rebecca Playne, Kathryn Jones, Bronwen Connor
Reprogramming technology holds great promise for the study and treatment of Parkinson's disease (PD) as patient-specific ventral midbrain dopamine (vmDA) neurons can be generated. This should facilitate the investigation of early changes occurring during PD pathogenesis, permitting the identification of new drug targets and providing a platform for drug screening. To date, most studies using reprogramming technology to study PD have employed induced pluripotent stem cells. Research into PD using direct reprogramming has been limited due to an inability to generate high yields of authentic human vmDA neurons...
2018: Journal of Stem Cells & Regenerative Medicine
Diti Chatterjee Bhowmick, Aleksandar Jeremic
Human islet amyloid polypeptide (hIAPP) is the principal constituent of amyloid deposits and toxic oligomers in the pancreatic islets. Together with hyperglycemia, hIAPP derived oligomers and aggregates are important culprits in type-2 diabetes mellitus. Here, we explored the role of cell's main proteolytic complex, the proteasome, in hIAPP turnover in normal and stressed β-cells evoked by chronic hyperglycemia.  Moderate inhibition (10-35%) of proteasome activity/function in cultured human islets by proteasome inhibitor lactacystin enhanced intracellular accumulation of hIAPP...
July 16, 2018: Journal of Biological Chemistry
T Guo, G Cao, Y Li, Z Zhang, J E Nör, B H Clarkson, J Liu
Previously, we reported that the fluorapatite (FA)-modified polycaprolactone (PCL) nanofiber could be an odontogenic/osteogenic inductive tissue-engineering scaffold by inducing stem cell differentiation and mineralization. The present study aimed to explore which of the signal pathways affected this differentiation and mineralization process. The Human Signal Transduction PathwayFinder RT2 Profiler PCR Array was used to analyze the involvement of potential signal transduction pathways during human dental pulp stem cell (DPSCs) osteogenic differentiation induced by FA-modified PCL nanofiber scaffolds...
July 1, 2018: Journal of Dental Research
Maheul Ploton, Claire Mazuy, Céline Gheeraert, Vanessa Dubois, Alexandre Berthier, Julie Dubois-Chevalier, Xavier Maréchal, Kadiombo Bantubungi, Hélène Diemer, Sarah Cianférani, Jean-Marc Strub, Audrey Helleboid-Chapman, Jérôme Eeckhoute, Bart Staels, Philippe Lefebvre
BACKGROUND & AIMS: Embedded into a complex signaling network that coordinates glucose uptake, usage and production, the nuclear bile acid receptor FXR is expressed in several glucose-processing organs including the liver. Hepatic gluconeogenesis is controlled through allosteric regulation of gluconeogenic enzymes and by glucagon/cAMP-dependent transcriptional regulatory pathways. We aimed to elucidate the role of FXR in the regulation of fasting hepatic gluconeogenesis. METHODS: The role of FXR in hepatic gluconeogenesis was assessed in vivo and in mouse primary hepatocytes...
July 5, 2018: Journal of Hepatology
Natalia Petersen, Thomas M Frimurer, Marianne Terndrup Pedersen, Kristoffer L Egerod, Nicolai J Wewer Albrechtsen, Jens J Holst, Anne Grapin-Botton, Kim B Jensen, Thue W Schwartz
BACKGROUND & AIMS: The glucagon like peptide 1 (GLP1) is produced by L cells in the intestine, and agonists of the GLP1 receptor are effective in treatment of diabetes. Levels of GLP1 increase with numbers of L cells. Agents that increase numbers of L cell might therefore be developed for treatment of diabetes. Ras homolog family member A (RHOA) signaling via Rho associated coiled-coil containing protein kinases 1 and 2 (ROCK1, ROCK2) controls cell differentiation, but it is not clear if this pathway regulates enteroendocrine differentiation in the intestinal epithelium...
June 20, 2018: Gastroenterology
Andrew M Kelleher, Jessica Milano-Foster, Susanta K Behura, Thomas E Spencer
Uterine glands are essential for pregnancy establishment. By employing forkhead box A2 (FOXA2)-deficient mouse models coupled with leukemia inhibitory factor (LIF) repletion, we reveal definitive roles of uterine glands in embryo implantation and stromal cell decidualization. Here we report that LIF from the uterine glands initiates embryo-uterine communication, leading to embryo attachment and stromal cell decidualization. Detailed histological and molecular analyses discovered that implantation crypt formation does not involve uterine glands, but removal of the luminal epithelium is delayed and subsequent decidualization fails in LIF-replaced glandless but not gland-containing FOXA2-deficient mice...
June 22, 2018: Nature Communications
Carla Mulas, Gloryn Chia, Kenneth Alan Jones, Andrew Christopher Hodgson, Giuliano Giuseppe Stirparo, Jennifer Nichols
Lineage segregation in the mouse embryo is a finely controlled process dependent upon coordination of signalling pathways and transcriptional responses. Here we employ a conditional deletion system to investigate embryonic patterning and lineage specification in response to loss of Oct4. We first observe ectopic expression of Nanog in Oct4-negative postimplantation epiblast cells. The expression domains of lineage markers are subsequently disrupted. Definitive endoderm expands at the expense of mesoderm; the anterior-posterior axis is positioned more distally and an ectopic posterior-like domain appears anteriorly, suggesting a role for Oct4 in maintaining the embryonic axis...
June 18, 2018: Development
Baolei Wang, Guangwei Liu, Lei Ding, Jun Zhao, Yun Lu
The present study determined the expression and biological functions of FOXA2 gene in colon cancer in tissues, cells and animals. A total of 66 patients with colon cancer were included in the present study. Using The Human Protein Atlas database, expression and distribution of FOXA2 in colon cancer tissues were analyzed. Using immunohistochemistry, the expression and distribution of FOXA2 in colon cancer cells were studied. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to determine the expression of FOXA2 mRNA in colon cancer tissues...
July 2018: Experimental and Therapeutic Medicine
Xiaopeng Zhou, Chiyuan Ma, Bin Hu, Yiqing Tao, Jingkai Wang, Xianpeng Huang, Tengfei Zhao, Bin Han, Hao Li, Chengzhen Liang, Qixin Chen, Fangcai Li
Adipose tissue-derived stem cell (ADSC)-based therapy is promising for the treatment of intervertebral disc (IVD) degeneration, but the difficulty in inducing nucleus pulposus (NP)-like differentiation limits its clinical applications. Forkhead box (Fox)-A2 is an essential transcription factor for the formation of a normal NP. We demonstrated that type II collagen stimulates NP-like differentiation of ADSCs, partly by increasing the expression of FoxA2. We constructed FoxA2-overexpressing and -knockdown ADSCs by using lentiviral vectors...
June 11, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Zhongwei Jia, Fangning Wan, Yao Zhu, Guohai Shi, Hailiang Zhang, Bo Dai, Dingwei Ye
Previous studies have demonstrated that several members of the Forkhead-box (FOX) family of genes are associated with tumor progression and metastasis. The objective of the current study was to screen candidate FOX family genes identified from analysis of molecular networks in clear cell renal cell carcinoma (ccRCC). The expression of FOX family genes as well as FOX family-associated genes was examined, and Kaplan-Meier survival analysis was performed in The Cancer Genome Atlas (TCGA) cohort (n=525). Patient characteristics, including sex, age, tumor diameter, laterality, tumor-node-metastasis, tumor grade, stage, white blood cell count, platelet count, the levels of hemoglobin, overall survival (OS) and disease-free survival (DFS), were collected for univariate and multivariate Cox proportional hazards ratio analyses...
June 2018: Oncology Letters
Maryam Khosravi, Negar Azarpira, Sara Shamdani, Suzzan Hojjat-Assari, Sina Naserian, Mohammad Hossein Karimi
Studying the profile of micro RNAs (miRs) elucidated the highest expressed miRs in hepatic differentiation. In this study, we investigated to clarify the role of three embryonic overexpressed miRs (miR-106a, miR-574-3p and miR-451) during hepatic differentiation of human umbilical cord derived mesenchymal stem cells (UC-MSCs). We furthermore, aimed to explore whether overexpression of any of these miRs alone is sufficient to induce the differentiation of the UC-MSCs into hepatocyte-like cells. UC-MSCs were transfected either alone or together with miR-106a, miR-574-3p and miR-451 and their potential hepatic differentiation and alteration in gene expression profile, morphological changes and albumin secretion ability were investigated...
August 15, 2018: Gene
Jorge Guzman-Lepe, Eduardo Cervantes-Alvarez, Alexandra Collin de l'Hortet, Yang Wang, Wendy M Mars, Yoshinao Oda, Yuki Bekki, Masahiro Shimokawa, Huanlin Wang, Tomoharu Yoshizumi, Yoshihiko Maehara, Aaron Bell, Ira J Fox, Kazuki Takeishi, Alejandro Soto-Gutierrez
The mechanisms by which the liver fails in end-stage liver disease remain elusive. Disruption of the transcription factor network in hepatocytes has been suggested to mediate terminal liver failure in animals. However, this hypothesis remains unexplored in human subjects. To study the relevance of transcription factor expression in terminal stages of chronic liver failure in humans, we analyzed the expression of liver-enriched transcription factors (LETFs) hepatocyte nuclear factor (HNF)4α, HNF1α, forkhead box protein A2 (FOXA2), CCAAT/enhancer-binding protein (CEBP)α, and CEBPβ...
May 2018: Hepatology Communications
Zhi Liu, Juncheng Dai, Hongbing Shen
Long noncoding RNAs (lncRNAs) are proposed to play essential roles in regulating gene transcription. Moreover, a subset has been implicated in modulating the expression of the nearby loci. Here we systematically evaluated the relationship between lncRNAs and their neighboring genes based on transcriptome expression profiles from 4900 samples across 12 cancer types. Our findings reveal that lncRNAs, especially those of high syntenic conservation across species, are spatially correlated with transcription factors across the genome...
September 2018: Biochimica et Biophysica Acta
Mohamed Salem, Jacob A O'Brien, Stefanie Bernaudo, Heba Shawer, Gang Ye, Jelena Brkić, Asma Amleh, Barbara C Vanderhyden, Basel Refky, Burton B Yang, Sergey N Krylov, Chun Peng
miRNAs play important roles in gene regulation, and their dysregulation is associated with many diseases, including epithelial ovarian cancer (EOC). In this study, we determined the expression and function of miR-590-3p in EOC. miR-590-3p levels were higher in high-grade carcinoma when compared with low-grade or tumors with low malignant potential. Interestingly, plasma levels of miR-590-3p were significantly higher in patients with EOC than in subjects with benign gynecologic disorders. Transient transfection of miR-590-3p mimics or stable transfection of mir-590 increased cell proliferation, migration, and invasion...
August 1, 2018: Cancer Research
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