scholarly journals KSR1 and EPHB4 Regulate Myc and PGC1β To Promote Survival of Human Colon Tumors

2016 ◽  
Vol 36 (17) ◽  
pp. 2246-2261 ◽  
Author(s):  
Jamie L. McCall ◽  
Drew Gehring ◽  
Beth K. Clymer ◽  
Kurt W. Fisher ◽  
Binita Das ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Posttranscriptional Regulation ◽  
Human Colon ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Selective Toxicity ◽  
Aberrant Expression ◽  
Peroxisome Proliferator Activated Receptor ◽  
Normal Tissues ◽  
Kinase Suppressor Of Ras

Identification and characterization of survival pathways active in tumor cells but absent in normal tissues provide opportunities to develop effective anticancer therapies with reduced toxicity to the patient. We show here that, like kinase suppressor of Ras 1 (KSR1), EPH (erythropoietin-producinghepatocellular carcinoma) receptor B4 (EPHB4) is aberrantly overexpressed in human colon tumor cell lines and selectively required for their survival. KSR1 and EPHB4 support tumor cell survival by promoting the expression of downstream targets, Myc and the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β). While KSR1 promotes the aberrant expression of Myc and the PGC1β protein via a posttranscriptional mechanism, EPHB4 has a greater effect on Myc and PGC1β expression via its ability to elevate mRNA levels. Subsequent analysis of the posttranscriptional regulation demonstrated that KSR1 promotes the translation of Myc protein. These findings reveal novel KSR1- and EPHB4-dependent signaling pathways supporting the survival of colorectal cancer cells through regulation of Myc and PGC1β, suggesting that inhibition of KSR1 or EPHB4 effectors may lead to selective toxicity in colorectal tumors.

scholarly journals AMPK Promotes Aberrant PGC1β Expression To Support Human Colon Tumor Cell Survival

2015 ◽  
Vol 35 (22) ◽  
pp. 3866-3879 ◽  
Author(s):  
Kurt W. Fisher ◽  
Binita Das ◽  
Hyun Seok Kim ◽  
Beth K. Clymer ◽  
Drew Gehring ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Survival ◽  
Human Colon ◽  
Colon Tumor ◽  
Peroxisome Proliferator ◽  
Specific Expression ◽  
Peroxisome Proliferator Activated Receptor ◽  
Tumor Cell Survival ◽  
Kinase Suppressor Of Ras ◽  
Colon Tumor Cell

A major goal of cancer research is the identification of tumor-specific vulnerabilities that can be exploited for the development of therapies that are selectively toxic to the tumor. We show here that the transcriptional coactivators peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β) and estrogen-related receptor α (ERRα) are aberrantly expressed in human colon cell lines and tumors. With kinase suppressor of Ras 1 (KSR1) depletion as a reference standard, we usedfunctionalsignatureontology (FUSION) analysis to identify the γ1 subunit of AMP-activated protein kinase (AMPK) as an essential contributor to PGC1β expression and colon tumor cell survival. Subsequent analysis revealed that a subunit composition of AMPK (α2β2γ1) is preferred for colorectal cancer cell survival, at least in part, by stabilizing the tumor-specific expression of PGC1β. In contrast, PGC1β and ERRα are not detectable in nontransformed human colon epithelial cells, and depletion of the AMPKγ1 subunit has no effect on their viability. These data indicate that Ras oncogenesis relies on the aberrant activation of a PGC1β-dependent transcriptional pathway via a specific AMPK isoform.

Thyroid hormone is required for the phenotype transitions induced by the pharmacological inhibition of calcineurin in adult soleus muscle of rats

2008 ◽  
Vol 294 (1) ◽  
pp. E69-E77 ◽  
Author(s):  
Nathalie Koulmann ◽  
Lahoucine Bahi ◽  
Florence Ribera ◽  
Hervé Sanchez ◽  
Bernard Serrurier ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Soleus Muscle ◽  
Hormone Deficiency ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Thyroid State ◽  
Novel Approach ◽  
A Subunit ◽  
Calcineurin Inhibition

The present experiment was designed to examine the effects of hypothyroidism and calcineurin inhibition induced by cyclosporin A (CsA) administration on both contractile and metabolic soleus muscle phenotypes, with a novel approach to the signaling pathway controlling mitochondrial biogenesis. Twenty-eight rats were randomly assigned to four groups, normothyroid, hypothyroid, and orally treated with either CsA (25 mg/kg, N-CsA and H-CsA) or vehicle (N-Vh and H-Vh), for 3 wk. Muscle phenotype was estimated by the MHC profile and activities of oxidative and glycolytic enzymes. We measured mRNA levels of the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), the major regulator of mitochondrial content. We also studied the expression of the catalytic A-subunit of calcineurin (CnA) both at protein and transcript levels and mRNA levels of modulatory calcineurin inhibitor proteins (MCIP)-1 and -2, which are differentially regulated by calcineurin activity and thyroid hormone, respectively. CsA-administration induced a slow-to-fast MHC transition limited to the type IIA isoform, which is associated with increased oxidative capacities. Hypothyroidism strongly decreased both the expression of fast MHC isoforms and oxidative capacities. Effects of CsA administration on muscle phenotype were blocked in conditions of thyroid hormone deficiency. Changes in the oxidative profile were strongly related to PGC-1α changes and associated with phosphorylation of p38 MAPK. Calcineurin and MCIPs mRNA levels were decreased by both hypothyroidism and CsA without additive effects. Taken together, these results suggest that adult muscle phenotype is primarily under the control of thyroid state. Physiological levels of thyroid hormone are required for the effects of calcineurin inhibition on slow oxidative muscle phenotype.

scholarly journals Liver nuclear hormone receptor PPAR, LXR and RXR expression and blood lipid and glucose levels in susceptible and resistent to hepatocarcinogenesis strain of mice

2010 ◽  
Vol 56 (4) ◽  
pp. 480-489
Author(s):  
E.N. Pivovarova ◽  
N.V. Baginskaya ◽  
M.L. Perepechaeva ◽  
S.I. Ilnitskaya ◽  
M.I. Dushkin
Keyword(s):  
Tumor Development ◽  
Corticosterone Level ◽  
Blood Lipid ◽  
Nuclear Hormone Receptor ◽  
Mouse Strains ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mrna Content ◽  
Dd Mice

Earlier it was shown that male mice of the DD/He strain were highly susceptible to ortho-aminoasotoluene (OAT) induced hepatocarcinogenesis, and resistant to spontaneous liver tumor development as compared to the СС57BR/Mv strain. In the present work we have made a comparative investigation of peroxisome proliferator-activated receptor (PPAR), liver X-receptor (LXR) and retinoic X-receptor (RXR) mRNA levels in liver as well as concentrations of corticosterone, glucose, lipids and insulin in blood of male DD/He and СС57BR/Mv mice. Using the multiplex RT-PCR method it was found that PPAR-α, PPAR-γ, RXR-α and RXR-β mRNA content was essentially decreased in the liver of DD mice as compared to mice of the СС57BR strain. No significant interstrain differences of LXR-α and LXR-β mRNA content were found. In DD micetere was more then the 3-fold decrease of blood content of corticosterone, which is involved in PPAR and RXR regulation. DD mice demonstrated a significant decrease in blood serum glucose and insulin concentrations as well as higher reactivity to insulin as compared with СС57BR mice. Elevated blood total cholesterol and cholesterol HDL level were found in DD mice whereas triglyceride content was basically the same in both mouse strains. It is known that glucocorticoids, PPAR and RXR play crucial role in transcription regulation of inflammation response. Therefore our data allow to suggest that decreased corticosterone level in blood, PPAR and RXR mRNA content in liver of the DD strain may lead to induction of inflammation by OAT exposure, resulting in a high incidence of tumorigenesis in this strain.

Prenatal androgen excess alters the uterine peroxisome proliferator-activated receptor (PPAR) system

2019 ◽  
Vol 31 (8) ◽  
pp. 1401
Author(s):  
Silvana R. Ferreira ◽  
Leandro M. Vélez ◽  
Maria F. Heber ◽  
Giselle A. Abruzzese ◽  
Alicia B. Motta
Keyword(s):  
Fetal Programming ◽  
Female Offspring ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Androgen Excess ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peroxisome Proliferator Activated Receptors ◽  
Pg E2 ◽  
Prenatal Androgen

It is known that androgen excess induces changes in fetal programming that affect several physiological pathways. Peroxisome proliferator-activated receptors (PPARs) α, δ and γ are key mediators of female reproductive functions, in particular in uterine tissues. Thus, we aimed to study the effect of prenatal hyperandrogenisation on the uterine PPAR system. Rats were treated with 2mg testosterone from Day 16 to 19 of pregnancy. Female offspring (PH group) were followed until 90 days of life, when they were killed. The PH group exhibited an anovulatory phenotype. We quantified uterine mRNA levels of PPARα (Ppara), PPARδ (Ppard), PPARγ (Pparg), their regulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a) and nuclear receptor co-repressor 1 (Ncor1) and cyclo-oxygenase (COX)-2 (Ptgs2), and assessed the lipid peroxidation (LP) index and levels of glutathione (GSH) and prostaglandin (PG) E2. The PH group showed decreased levels of all uterine PPAR isoforms compared with the control group. In addition, PGE2 and Ptgs2 levels were increased in the PH group, which led to a uterine proinflammatory environment, as was LP, which led to a pro-oxidant status that GSH was not able to compensate for. These results suggest that prenatal exposure to androgen excess has a fetal programming effect that affects the gene expression of PPAR isoforms, and creates a misbalanced oxidant–antioxidant state and a proinflammatory status.

scholarly journals Exercise Training-Induced PPARβ Increases PGC-1α Protein Stability and Improves Insulin-Induced Glucose Uptake in Rodent Muscles

Nutrients ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 652 ◽  
Author(s):  
Ju-Sik Park ◽  
John O. Holloszy ◽  
Kijin Kim ◽  
Jin-Ho Koh
Keyword(s):  
Cytochrome C ◽  
Exercise Training ◽  
Protein Stability ◽  
Glucose Uptake ◽  
Citrate Synthase ◽  
Peroxisome Proliferator ◽  
Mitochondrial Enzymes ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor

This study aimed to investigate the long-term effects of training intervention and resting on protein expression and stability of peroxisome proliferator-activated receptor β/δ (PPARβ), peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α), glucose transporter type 4 (GLUT4), and mitochondrial proteins, and determine whether glucose homeostasis can be regulated through stable expression of these proteins after training. Rats swam daily for 3, 6, 9, 14, or 28 days, and then allowed to rest for 5 days post-training. Protein and mRNA levels were measured in the skeletal muscles of these rats. PPARβ was overexpressed and knocked down in myotubes in the skeletal muscle to investigate the effects of swimming training on various signaling cascades of PGC-1α transcription, insulin signaling, and glucose uptake. Exercise training (Ext) upregulated PPARβ, PGC-1α, GLUT4, and mitochondrial enzymes, including NADH-ubiquinone oxidoreductase (NUO), cytochrome c oxidase subunit I (COX1), citrate synthase (CS), and cytochrome c (Cyto C) in a time-dependent manner and promoted the protein stability of PPARβ, PGC-1α, GLUT4, NUO, CS, and Cyto C, such that they were significantly upregulated 5 days after training cessation. PPARβ overexpression increased the PGC-1α protein levels post-translation and improved insulin-induced signaling responsiveness and glucose uptake. The present results indicate that Ext promotes the protein stability of key mitochondria enzymes GLUT4, PGC-1α, and PPARβ even after Ext cessation.

Adult rats prenatally exposed to ethanol have increased gluconeogenesis and impaired insulin response of hepatic gluconeogenic genes

2006 ◽  
Vol 100 (2) ◽  
pp. 642-648 ◽  
Author(s):  
Xing-Hai Yao ◽  
Li Chen ◽  
B. L. Grégoire Nyomba
Keyword(s):  
Insulin Response ◽  
Insulin Injection ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Adult Rats ◽  
Peroxisome Proliferator Activated Receptor ◽  
Insulin Resistant ◽  
Adult Rat ◽  
Rat Offspring ◽  
Before And After

Rat offspring exposed to ethanol (EtOH rats) during pregnancy are insulin resistant, but it is unknown whether they have increased gluconeogenesis. To address this issue, we determined blood glucose and liver gluconeogenic genes, proteins, and enzyme activities before and after insulin administration in juvenile and adult EtOH rats and submitted adult EtOH rats to a pyruvate challenge. In juvenile rats, basal glucose; peroxisome proliferator-activated receptor-coactivator-1α protein and mRNA; and phospho enolpyruvate carboxykinase enzyme activity, protein, and mRNA were similar between groups. After insulin injection, these parameters failed to decrease in EtOH rats, but glucose decreased by 30% and gluconeogenic enzymes, proteins, and mRNAs decreased by 50–70% in control rats. In adult offspring, basal peroxisome proliferator-activated receptor-coactivator-1α protein and mRNA levels were 40–80% higher in EtOH rats than in controls. Similarly, basal phospho enolpyruvate carboxykinase activity, protein, and mRNA were ∼1.8-fold greater in EtOH rats than in controls. These parameters decreased by ∼50% after insulin injection in control rats, but they remained unchanged in EtOH rats. After insulin injection in the adult rats, glucose decreased by 60% in controls but did not decrease significantly in EtOH rats. A subset of adult EtOH rats had fasting hyperglycemia and an exaggerated glycemic response to pyruvate compared with controls. The data indicate that, after prenatal EtOH exposure, the expression of gluconeogenic genes is exaggerated in adult rat offspring and is insulin resistant in both juvenile and adult rats, explaining increased gluconeogenesis. These alterations persist through adulthood and may contribute to the pathogenesis of Type 2 diabetes after exposure to EtOH in utero.

scholarly journals Cyclin G2 Regulates Adipogenesis through PPARγ Coactivation

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5247-5254 ◽  
Author(s):  
Victor Aguilar ◽  
Jean-Sébastien Annicotte ◽  
Xavier Escote ◽  
Joan Vendrell ◽  
Dominique Langin ◽  
...  
Keyword(s):  
Adipocyte Differentiation ◽  
Luciferase Reporter ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Cell Cycle Regulators ◽  
Luciferase Reporter Gene ◽  
Peroxisome Proliferator Activated Receptor ◽  
Cyclin G2 ◽  
Regulatory Effects

Cell cycle regulators such as cyclins, cyclin-dependent kinases, or retinoblastoma protein play important roles in the differentiation of adipocytes. In the present paper, we investigated the role of cyclin G2 as a positive regulator of adipogenesis. Cyclin G2 is an unconventional cyclin which expression is up-regulated during growth inhibition or apoptosis. Using the 3T3-F442A cell line, we observed an up-regulation of cyclin G2 expression at protein and mRNA levels throughout the process of cell differentiation, with a further induction of adipogenesis when the protein is transiently overexpressed. We show here that the positive regulatory effects of cyclin G2 in adipocyte differentiation are mediated by direct binding of cyclin G2 to peroxisome proliferator-activated receptor γ (PPARγ), the key regulator of adipocyte differentiation. The role of cyclin G2 as a novel PPARγ coactivator was further demonstrated by chromatin immunoprecipitation assays, which showed that the protein is present in the PPARγ-responsive element of the promoter of aP2, which is a PPARγ target gene. Luciferase reporter gene assays, showed that cyclin G2 positively regulates the transcriptional activity of PPARγ. The role of cyclin G2 in adipogenesis is further underscored by its increased expression in mice fed a high-fat diet. Taken together, our results demonstrate a novel role for cyclin G2 in the regulation of adipogenesis.

Levels of mRNA of iLBP family genes and retinoic acid receptors in embryonal tumors in children.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22517-e22517
Author(s):  
Olga P. Popovyan ◽  
Oleg I. Kit ◽  
Dmitrii S. Potemkin ◽  
Natalya N. Timoshkina ◽  
Sergei A. Kuznetsov
Keyword(s):  
Retinoic Acid ◽  
Solid Tumors ◽  
Cdna Libraries ◽  
Mrna Levels ◽  
Aberrant Expression ◽  
Genetic Characteristics ◽  
Normal Tissues ◽  
Pediatric Solid Tumors ◽  
Genes Encoding ◽  
Expression Activity

e22517 Background: Neuro- and nephroblastoma are the most common pediatric solid tumors. Their varying clinical behavior determines challenging prognosis and choice of treatment tactics. Along with many clinical parameters, the genetic characteristics of tumor cells appear promising. Methods: The study included patients diagnosed with neuroblastoma (n = 10) and nephroblastoma (n = 10) (median age from 2 months to 8 years; 10 boys and 10 girls). Total RNA was extracted from paired tumor/normal samples using the miRNeasy Mini Kit (Qiagen, USA) and cDNA libraries obtained with the Reverta-L kit. Expression of the CRABP1, CRABP2, FABP4, FABP5, RAR, RXRA, RXRB, and PPARD genes was evaluated by RT-PCR on the CFX96 amplifier (Bio-Rad, USA). GAPDH and B2M were reference loci. Relative expression (Exp) was calculated by the 2-ΔCt method. Results: The qPCR-RT showed a significant increase in the transcriptional activity in both tumors, compared to normal tissues, for the FABP4, FABP5, and RXRA loci (p < 0.01). Interestingly, we observed multidirectional changes in mRNA levels in neuroblastomas and nephroblastomas for the CRABP1, RAR, and PPARD loci. Unlike solid tumors of adult patients, the expression activity of the CRABP1 gene either did not differ from the conditional norm (in nephroblastoma), or significantly dropped to 70% (in neuroblastoma). In contrast to adult solid tumors, the CRABP1 gene expression activity in children was normal (in nephroblastoma) or decreased significantly up to 70% (in neuroblastoma). Conclusions: The pilot study revealed differentiating aberrant expression of genes encoding the family of retinoic acid transporters and receptors in pediatric neuroblastomas and nephroblastomas. This may be essential for choosing the optimal treatment volume and establishing a prognosis and resistance to chemotherapy in patients with these tumors.

scholarly journals Expression of peroxisome proliferator-activated receptor-γ in macrophage suppresses experimentally induced colitis

2007 ◽  
Vol 292 (2) ◽  
pp. G657-G666 ◽  
Author(s):  
Yatrik M. Shah ◽  
Keiichirou Morimura ◽  
Frank J. Gonzalez
Keyword(s):  
Clinical Symptoms ◽  
Body Weight Loss ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Wild Type ◽  
Targeted Disruption ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Cytokine Analysis ◽  
Increased Susceptibility

Peroxisome proliferator-activated receptor-γ (PPAR-γ) has been shown to be a protective transcription factor in mouse models of inflammatory bowel disease (IBD). PPAR-γ is expressed in several different cell types, and mice with a targeted disruption of the PPAR-γ gene in intestinal epithelial cells demonstrated increased susceptibility to dextran sulfate sodium (DSS)-induced IBD. However, the highly selective PPAR-γ ligand rosiglitazone decreased the severity of DSS-induced colitis and suppressed cytokine production in both PPAR-γ intestinal specific null mice and wild-type littermates. Therefore the role of PPAR-γ in different tissues and their contribution to the pathogenesis of IBD still remain unclear. Mice with a targeted disruption of PPAR-γ in macrophages (PPAR-γΔMφ) and wild-type littermates (PPAR-γF/F) were administered 2.5% DSS in drinking water to induce IBD. Typical clinical symptoms were evaluated on a daily basis, and proinflammatory cytokine analysis was performed. PPAR-γΔMφ mice displayed an increased susceptibility to DSS-induced colitis compared with wild-type littermates, as defined by body weight loss, diarrhea, rectal bleeding score, colon length, and histology. IL-1β, CCR2, MCP-1, and inducible nitric oxide synthase mRNA levels in colons of PPAR-γΔMφ mice treated with DSS were higher than in similarly treated PPAR-γF/F mice. The present study has identified a novel protective role for macrophage PPAR-γ in the DSS-induced IBD model. The data suggest that PPAR-γ regulates recruitment of macrophages to inflammatory foci in the colon.

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