scholarly journals Men1 maintains exocrine pancreas homeostasis in response to inflammation and oncogenic stress

2020 ◽  
Vol 117 (12) ◽  
pp. 6622-6629 ◽  
Author(s):  
Amanda R. Wasylishen ◽  
Chang Sun ◽  
Gilda P. Chau ◽  
Yuan Qi ◽  
Xiaoping Su ◽  
...  
Keyword(s):  
Exocrine Pancreas ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Direct Evidence ◽  
Immune Cell ◽  
Cytokeratin 19 ◽  
Severe Damage ◽  
Oncogenic Stress ◽  
Genetic Mouse Models

A more comprehensive understanding of the molecular mechanisms underlying pancreatic diseases, including pancreatitis and cancer, is essential to improve clinical management. MEN1 has established roles in epigenetic regulation and tumor suppression in the endocrine pancreas; however, intriguing recent data suggest MEN1 may also function in the exocrine pancreas. Using physiologically relevant genetic mouse models, we provide direct evidence that Men1 is essential for exocrine pancreas homeostasis in response to inflammation and oncogenic stress. Men1 loss causes increased injury and impaired regeneration following acute caerulein-induced pancreatitis, leading to more severe damage, loss of the normal acinar compartment, and increased cytokeratin 19-positive metaplasias and immune cell infiltration. We further demonstrate the Men1 protein is stabilized in response to insult, and loss of Men1 is associated with the overexpression of proinflammatory Jund target genes, suggesting that loss of Men1-mediated repression of Jund activity is, at least in part, responsible for the impaired response. Finally, we demonstrate thatMen1loss significantly accelerates mutant Kras-dependent oncogenesis. Combined, this work establishes Men1 as an important mediator of pancreas homeostasis in vivo.

scholarly journals STAT3 and HIF1α cooperatively mediate the transcriptional and physiological responses to hypoxia

2021 ◽  
Author(s):  
Alberto Dinarello ◽  
Riccardo Massimiliano Betto ◽  
Chiara Cioccarelli ◽  
Linda Diamante ◽  
Giacomo Meneghetti ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
Immune Cell ◽  
Large Fraction ◽  
Physiological Responses ◽  
Embryonic Stem ◽  
Knock Out ◽  
Two Factors ◽  
Cell Mobilization

STAT3 and HIF1α are two fundamental transcription factors involved in many merging properties, like angiogenesis, metabolism, and cell differentiation. Notably, under pathological conditions, the two factors have been shown to interact genetically, but both the molecular mechanisms underlying such interactions and their relevance under physiological conditions remains unclear. Here we report that STAT3 is required for the HIF1α-dependent response to hypoxia. In Stat3 knock-out pluripotent embryonic stem cells (ESCs), a large fraction of HIF1α target genes is not induced by hypoxia. Mechanistically, STAT3 does not regulate neither HIF1α expression nor stability, rather, it physically interacts with it in the nucleus. In vivo, we observed that both genetic and chemical inactivation of Stat3 blunted physiological responses to hypoxia, such as angiogenesis, erythropoiesis, and immune cell mobilization. Such defects were accompanied with faulty transcriptional activity of HIF1α. In sum, our data reveal that STAT3 and HIF1α cooperatively mediate the physiological response to hypoxia.

scholarly journals Cdx2 regulates immune cell infiltration in the intestine

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Simon Chewchuk ◽  
Sanzida Jahan ◽  
David Lohnes
Keyword(s):  
Intestinal Epithelium ◽  
Target Genes ◽  
Immune Cell ◽  
Cell Number ◽  
Macrophage Infiltration ◽  
Intestinal Homeostasis ◽  
Chronic Inflammatory Response ◽  
Complex Protein ◽  
Inflammatory Phenotype

AbstractThe intestinal epithelium is a unique tissue, serving both as a barrier against pathogens and to conduct the end digestion and adsorption of nutrients. As regards the former, the intestinal epithelium contains a diverse repertoire of immune cells, including a variety of resident lymphocytes, macrophages and dendritic cells. These cells serve a number of roles including mitigation of infection and to stimulate regeneration in response to damage. The transcription factor Cdx2, and to a lesser extent Cdx1, plays essential roles in intestinal homeostasis, and acts as a context-dependent tumour suppressor in colorectal cancer. Deletion of Cdx2 from the murine intestinal epithelium leads to macrophage infiltration resulting in a chronic inflammatory response. However the mechanisms by which Cdx2 loss evokes this response are poorly understood. To better understand this relationship, we used a conditional mouse model lacking all intestinal Cdx function to identify potential target genes which may contribute to this inflammatory phenotype. One such candidate encodes the histocompatability complex protein H2-T3, which functions to regulate intestinal iCD8α lymphocyte activity. We found that Cdx2 occupies the H3-T3 promoter in vivo and directly regulates its expression via a Cdx response element. Loss of Cdx function leads to a rapid and pronounced attenuation of H2-T3, followed by a decrease in iCD8α cell number, an increase in macrophage infiltration and activation of pro-inflammatory cascades. These findings suggest a previously unrecognized role for Cdx in intestinal homeostasis through H2-T3-dependent regulation of iCD8α cells.

scholarly journals Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Andrew P. Sawaya ◽  
Rivka C. Stone ◽  
Stephen R. Brooks ◽  
Irena Pastar ◽  
Ivan Jozic ◽  
...  
Keyword(s):  
Wound Healing ◽  
Inflammatory Response ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Diabetic Mouse ◽  
Transcriptional Networks ◽  
Life Threatening ◽  
Diabetic Wound Healing ◽  
Diabetic Wounds

Abstract Diabetic foot ulcers (DFUs) are a life-threatening disease that often result in lower limb amputations and a shortened lifespan. However, molecular mechanisms contributing to the pathogenesis of DFUs remain poorly understood. We use next-generation sequencing to generate a human dataset of pathogenic DFUs to compare to transcriptional profiles of human skin and oral acute wounds, oral as a model of “ideal” adult tissue repair due to accelerated closure without scarring. Here we identify major transcriptional networks deregulated in DFUs that result in decreased neutrophils and macrophages recruitment and overall poorly controlled inflammatory response. Transcription factors FOXM1 and STAT3, which function to activate and promote survival of immune cells, are inhibited in DFUs. Moreover, inhibition of FOXM1 in diabetic mouse models (STZ-induced and db/db) results in delayed wound healing and decreased neutrophil and macrophage recruitment in diabetic wounds in vivo. Our data underscore the role of a perturbed, ineffective inflammatory response as a major contributor to the pathogenesis of DFUs, which is facilitated by FOXM1-mediated deregulation of recruitment of neutrophils and macrophages, revealing a potential therapeutic strategy.

Cellular and molecular mechanisms of hypoxia-inducible factor driven vascular remodeling

2007 ◽  
Vol 97 (05) ◽  
pp. 774-787 ◽  
Author(s):  
Norbert Weissmann ◽  
Friedrich Grimminger ◽  
Werner Seeger ◽  
Frank Rose ◽  
Jörg Hänze
Keyword(s):  
Vascular Remodeling ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Genetic Manipulation ◽  
Hypoxia Inducible Factor ◽  
Ischemic Disease ◽  
Hypoxic Conditions ◽  
Concomitant Reduction ◽  
Adaptive Processes

SummaryHypoxia-inducible factor (HIF) is an oxygen-dependent transcription factor that activates a diverse set of target genes, the products of which are involved in adaptive processes to hypoxia. Employing genetic manipulation of HIF expression, in-vivo and cellular studies have focused on HIF as a crucial factor affecting hypoxia-induced vascular remodeling.Vascular remodeling comprises processes which establish and improve blood vessel supply such as vasculogenesis, angiogenesis and arteriogenesis. These processes are observed during ontogenesis, tumor progression, ischemic disease or physical training. Furthermore, under hypoxic conditions, a pulmonary-specific type of vascular remodeling called pulmonary arterial remodeling occurs that is characterized by thickening of the vessel wall with a concomitant reduction in the vessel lumen area, thereby limiting blood flow.This response results in pulmonary hypertension with right ventricular hypertrophy, a lethal disease. In this review, we summarize and discuss mechanisms by which HIF interferes with the different vascular remodeling processes.

scholarly journals Genetic Mouse Models as In Vivo Tools for Cholangiocarcinoma Research

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1868 ◽  
Author(s):  
Oihane Erice ◽  
Adrian Vallejo ◽  
Mariano Ponz-Sarvise ◽  
Michael Saborowski ◽  
Arndt Vogel ◽  
...  
Keyword(s):  
Mouse Models ◽  
Molecular Mechanisms ◽  
Complex Disease ◽  
Current Knowledge ◽  
Genetic Alterations ◽  
In Vivo Model ◽  
In Vivo Models ◽  
Dismal Prognosis ◽  
Genetic Mouse Models

Cholangiocarcinoma (CCA) is a genetically and histologically complex disease with a highly dismal prognosis. A deeper understanding of the underlying cellular and molecular mechanisms of human CCA will increase our current knowledge of the disease and expedite the eventual development of novel therapeutic strategies for this fatal cancer. This endeavor is effectively supported by genetic mouse models, which serve as sophisticated tools to systematically investigate CCA pathobiology and treatment response. These in vivo models feature many of the genetic alterations found in humans, recapitulate multiple hallmarks of cholangiocarcinogenesis (encompassing cell transformation, preneoplastic lesions, established tumors and metastatic disease) and provide an ideal experimental setting to study the interplay between tumor cells and the surrounding stroma. This review is intended to serve as a compendium of CCA mouse models, including traditional transgenic models but also genetically flexible approaches based on either the direct introduction of DNA into liver cells or transplantation of pre-malignant cells, and is meant as a resource for CCA researchers to aid in the selection of the most appropriate in vivo model system.

scholarly journals A Dominant-Negative Thyroid Hormone Receptor Blocks Amphibian Metamorphosis by Retaining Corepressors at Target Genes

2003 ◽  
Vol 23 (19) ◽  
pp. 6750-6758 ◽  
Author(s):  
Daniel R. Buchholz ◽  
Shao-Chung Victor Hsia ◽  
Liezhen Fu ◽  
Yun-Bo Shi
Keyword(s):  
Thyroid Hormone ◽  
Molecular Mechanism ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Dominant Negative ◽  
Developmental Expression ◽  
Dual Function ◽  
Function Model ◽  
Amphibian Metamorphosis

ABSTRACT The total dependence of amphibian metamorphosis on thyroid hormone (T3) provides a unique vertebrate model for studying the molecular mechanism of T3 receptor (TR) function in vivo. In vitro transcription and developmental expression studies have led to a dual function model for TR in amphibian development, i.e., TRs act as transcriptional repressors in premetamorphic tadpoles and as activators during metamorphosis. We examined molecular mechanisms of TR action in T3-induced metamorphosis by using dominant-negative receptors (dnTR) ubiquitously expressed in transgenic Xenopus laevis. We showed that T3-induced activation of T3 target genes and morphological changes are blocked in dnTR transgenic animals. By using chromatin immunoprecipitation, we show that dnTR bound to target promoters, which led to retention of corepressors and continued histone deacetylation in the presence of T3. These results thus provide direct in vivo evidence for the first time for a molecular mechanism of altering gene expression by a dnTR. The correlation between dnTR-mediated gene repression and inhibition of metamorphosis also supports a key aspect of the dual function model for TR in development: during T3-induced metamorphosis, TR functions as an activator via release of corepressors and promotion of histone acetylation and gene activation.

scholarly journals Impact of Reduced ATGL-Mediated Adipocyte Lipolysis on Obesity-Associated Insulin Resistance and Inflammation in Male Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3610-3624 ◽  
Author(s):  
Gabriele Schoiswohl ◽  
Maja Stefanovic-Racic ◽  
Marie N. Menke ◽  
Rachel C. Wills ◽  
Beth A. Surlow ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Target Genes ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Peroxisome Proliferator ◽  
Immune Cell Infiltration ◽  
Lipid Uptake ◽  
Peroxisome Proliferator Activated Receptor ◽  
Triacylglycerol Hydrolysis

Emerging evidence suggests that impaired regulation of adipocyte lipolysis contributes to the proinflammatory immune cell infiltration of metabolic tissues in obesity, a process that is proposed to contribute to the development and exacerbation of insulin resistance. To test this hypothesis in vivo, we generated mice with adipocyte-specific deletion of adipose triglyceride lipase (ATGL), the rate-limiting enzyme catalyzing triacylglycerol hydrolysis. In contrast to previous models, adiponectin-driven Cre expression was used for targeted ATGL deletion. The resulting adipocyte-specific ATGL knockout (AAKO) mice were then characterized for metabolic and immune phenotypes. Lean and diet-induced obese AAKO mice had reduced adipocyte lipolysis, serum lipids, systemic lipid oxidation, and expression of peroxisome proliferator-activated receptor alpha target genes in adipose tissue (AT) and liver. These changes did not increase overall body weight or fat mass in AAKO mice by 24 weeks of age, in part due to reduced expression of genes involved in lipid uptake, synthesis, and adipogenesis. Systemic glucose and insulin tolerance were improved in AAKO mice, primarily due to enhanced hepatic insulin signaling, which was accompanied by marked reduction in diet-induced hepatic steatosis as well as hepatic immune cell infiltration and activation. In contrast, although adipocyte ATGL deletion reduced AT immune cell infiltration in response to an acute lipolytic stimulus, it was not sufficient to ameliorate, and may even exacerbate, chronic inflammatory changes that occur in AT in response to diet-induced obesity.

scholarly journals Exosomal miR-1290 promotes angiogenesis in hepatocellular carcinoma via targeting SMEK1

2020 ◽  
Author(s):  
Qiong Wang ◽  
Guanwen Wang ◽  
Lianjie Niu ◽  
Shaorong Zhao ◽  
Jianjun Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Endothelial Cells ◽  
Tumor Angiogenesis ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Primary Liver Cancer ◽  
Tumor Model ◽  
Tube Formation ◽  
Luciferase Reporter

Abstract Background: Hepatocellular carcinoma (HCC), the most common primary liver cancer, rely on the formation of new blood vessel for growth and frequent intrahepatic and extrahepatic metastasis. Therefore, it is important to explore the underlying molecular mechanisms of tumor angiogenesis of HCC. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, the potential roles of tumor-derived exosomal microRNAs in regulating tumor angiogenesis remain to be elucidated. Methods: MiRNome sequencing was performed to uncover the miRNAs that are dysregulated in HCC patient serum-derived exosomes. Expression levels of miR-1290 in tissues and cells were determined by quantitative real-time PCR. The effect of mir-1290 on proliferation was evaluated by CCK-8 assay. The angiogenic ability of cells were determined by transwell, wound-healing, tube formation and matrigel plug assays. SMMC-7721 xenograft tumor model was established in NOD-SCID nude mice using miR-1290 and NC antagomirs to determin the angiogenic effect of mir-1290 in vivo. Target protein expression was determined by western blotting. Dual luciferase reporter assay was performed to confirm the action of miR-1290 on downstream target genes including SMEK1. Results are reported as means ± S.D. and differences were tested for significance using 2-sided Student’s t-test.Results: In this study, our miRNome sequencing demonstrated that miR-1290 was overexpressed in HCC patient serum-derived exosomes, and we found that delivery of miR-1290 into human endothelial cells enhanced their angiogenic ability. Our results further revealed that SMEK1 is a direct target of miR-1290 in endothelial cells. MiR-1290 exerted its pro-angiogenic function, at least in part, by alleviating the inhibition of VEGFR2 phosphorylation done by SMEK1. Conclusions: Collectively, our findings provide evidence that miR-1290 is overexpressed in HCC and promotes tumor angiogenesis via exosomal secretion, implicating its potential role as a therapeutic target for HCC.

scholarly journals Unveiling Tumor Microenvironment Interactions Using Zebrafish Models

2021 ◽  
Vol 7 ◽  
Author(s):  
Reid Loveless ◽  
Chloe Shay ◽  
Yong Teng
Keyword(s):  
Tumor Microenvironment ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Genetic Manipulation ◽  
Innate Immune ◽  
Model Systems ◽  
Cytokine Signaling ◽  
Adult Zebrafish ◽  
Metastatic Cascade

The tumor microenvironment (TME) is a rich and active arena that is strategically evolved overtime by tumors to promote their survival and dissemination. Over the years, attention has been focused to characterize and identify the tumor-supporting roles and subsequent targeting potentials of TME components. Nevertheless, recapitulating the human TME has proved inherently challenging, leaving much to be explored. In this regard, in vivo model systems like zebrafish, with its optical clarity, ease of genetic manipulation, and high engraftment, have proven to be indispensable for TME modeling and investigation. In this review, we discuss the recent ways by which zebrafish models have lent their utility to provide new insights into the various cellular and molecular mechanisms driving TME dynamics and tumor support. Specifically, we report on innate immune cell interactions, cytokine signaling, metastatic plasticity, and other processes within the metastatic cascade. In addition, we reflect on the arrival of adult zebrafish models and the potential of patient-derived xenografts.

scholarly journals Molecular Mechanisms of Leukocyte Migration and Its Potential Targeting—Lessons Learned From MKL1/SRF-Related Primary Immunodeficiency Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Evelien G. G. Sprenkeler ◽  
Carla Guenther ◽  
Imrul Faisal ◽  
Taco W. Kuijpers ◽  
Susanna C. Fagerholm
Keyword(s):  
Immune System ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Serum Response Factor ◽  
Cell Function ◽  
Immune Cell ◽  
Leukocyte Adhesion ◽  
Adaptive Immune System ◽  
Lessons Learned ◽  
Megakaryoblastic Leukemia

Megakaryoblastic leukemia 1 (MKL1) deficiency is one of the most recently discovered primary immunodeficiencies (PIDs) caused by cytoskeletal abnormalities. These immunological “actinopathies” primarily affect hematopoietic cells, resulting in defects in both the innate immune system (phagocyte defects) and adaptive immune system (T-cell and B-cell defects). MKL1 is a transcriptional coactivator that operates together with serum response factor (SRF) to regulate gene transcription. The MKL/SRF pathway has been originally described to have important functions in actin regulation in cells. Recent results indicate that MKL1 also has very important roles in immune cells, and that MKL1 deficiency results in an immunodeficiency affecting the migration and function of primarily myeloid cells such as neutrophils. Interestingly, several actinopathies are caused by mutations in genes which are recognized MKL(1/2)-dependent SRF-target genes, namely ACTB, WIPF1, WDR1, and MSN. Here we summarize these and related (ARPC1B) actinopathies and their effects on immune cell function, especially focusing on their effects on leukocyte adhesion and migration. Furthermore, we summarize recent therapeutic efforts targeting the MKL/SRF pathway in disease.

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