scholarly journals DEF-1, a Novel Src SH3 Binding Protein That Promotes Adipogenesis in Fibroblastic Cell Lines

1999 ◽  
Vol 19 (3) ◽  
pp. 2330-2337 ◽  
Author(s):  
Frederick J. King ◽  
Erding Hu ◽  
David F. Harris ◽  
Pasha Sarraf ◽  
Bruce M. Spiegelman ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Ectopic Expression ◽  
Signal Transduction Pathway ◽  
Bovine Brain ◽  
Cellular Growth ◽  
Affinity Column ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Efficient Induction ◽  
Signal Transduction Proteins

ABSTRACT The Src homology 3 (SH3) motif is found in numerous signal transduction proteins involved in cellular growth and differentiation. We have purified and cloned a novel protein, DEF-1 (differentiation-enhancing factor), from bovine brain by using a Src SH3 affinity column. Ectopic expression of DEF-1 in fibroblasts resulted in the differentiation of a significant fraction of the culture into adipocytes. This phenotype appears to be related to the induction of the transcription factor peroxisome proliferator-activated receptor γ (PPARγ), since DEF-1 NIH 3T3 cells demonstrated augmented levels of PPARγ mRNA and, when treated with activating PPARγ ligands, efficient induction of differentiation. Further evidence for a role for DEF-1 in adipogenesis was provided by heightened expression of DEF-1 mRNA in adipose tissue isolated fromobese and diabetes mice compared to that in tissue isolated from wild-type mice. However, DEF-1 mRNA was detected in multiple tissues, suggesting that the signal transduction pathway(s) in which DEF-1 is involved is not limited to adipogenesis. These results suggest that DEF-1 is an important component of a signal transduction process that is involved in the differentiation of fibroblasts and possibly of other types of cells.

scholarly journals PPAR, PTEN, and the Fight against Cancer

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-6 ◽  
Author(s):  
Rosemary E. Teresi ◽  
Kristin A. Waite
Keyword(s):  
Tumor Suppressor ◽  
Hormone Receptors ◽  
Susceptibility Gene ◽  
Genetic Alterations ◽  
Cellular Growth ◽  
In Vivo Studies ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Peroxisome proliferator-activated receptor gamma (PPAR) is a ligand-activated transcription factor, which belongs to the family of nuclear hormone receptors. Recent in vitro studies have shown that PPAR can regulate the transcription ofphosphatase and tensin homolog on chromosometen(PTEN), a known tumor suppressor.PTENis a susceptibility gene for a number of disorders, including breast and thyroid cancer. Activation of PPAR through agonists increases functional PTEN protein levels that subsequently induces apoptosis and inhibits cellular growth, which suggests that PPAR may be a tumor suppressor. Indeed, several in vivo studies have demonstrated that genetic alterations of PPAR can promote tumor progression. These results are supported by observations of the beneficial effects of PPAR agonists in the in vivo cancer setting. These studies signify the importance of PPAR andPTEN's interaction in cancer prevention.

Agouti regulates adipocyte transcription factors

2001 ◽  
Vol 280 (4) ◽  
pp. C954-C961 ◽  
Author(s):  
Randall L. Mynatt ◽  
Jacqueline M. Stephens
Keyword(s):  
Adipose Tissue ◽  
Transgenic Mice ◽  
Ectopic Expression ◽  
Peroxisome Proliferator ◽  
Paracrine Factor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Skeletal Mass ◽  
Ppar Γ ◽  
Obesity And Diabetes

Agouti is a secreted paracrine factor that regulates pigmentation in hair follicle melanocytes. Several dominant mutations cause ectopic expression of agouti, resulting in a phenotype characterized by yellow fur, adult-onset obesity and diabetes, increased linear growth and skeletal mass, and increased susceptibility to tumors. Humans also produce agouti protein, but the highest levels of agouti in humans are found in adipose tissue. To mimic the human agoutiexpression pattern in mice, transgenic mice (aP2-agouti) that express agouti in adipose tissue were generated. The transgenic mice develop a mild form of obesity, and they are sensitized to the action of insulin. We correlated the levels of specific regulators of insulin signaling and adipocyte differentiation with these phenotypic changes in adipose tissue. Signal transducers and activators of transcription (STAT)1, STAT3, and peroxisome proliferator-activated receptor (PPAR)-γ protein levels were elevated in the transgenic mice. Treatment of mature 3T3-L1 adipocytes recapitulated these effects. These data demonstrate that agouti has potent effects on adipose tissue. We hypothesize that agouti increases adiposity and promotes insulin sensitivity by acting directly on adipocytes via PPAR-γ.

Molecular mechanisms of signal transduction via adiponectin and adiponectin receptors

2010 ◽  
Vol 391 (9) ◽  
Author(s):  
John T. Heiker ◽  
David Kosel ◽  
Annette G. Beck-Sickinger
Keyword(s):  
Signal Transduction ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Molecular Characteristics ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Downstream Signaling ◽  
Specific Effects ◽  
Intracellular Binding ◽  
Functional Mechanisms

Abstract The adipocytokine adiponectin and its receptor (AdipoR) comprise a new receptor-ligand system that is involved in a variety of clinically important morbidities such as obesity, type 2 diabetes and cardiovascular diseases. Adiponectin exerts a multitude of beneficial and tissue specific effects depending on its unique, tightly regulated multimerization behavior. Post-translational modifications are essential for the multimer assembly before secretion and protein stability in the circulation. AdipoR1 and 2 have been discovered as a new class of heptahelix receptors structurally and functionally distinct from G-protein-coupled receptors. Both AdipoRs bind adiponectin and the downstream signaling of both AdipoRs is mediated mainly by phosphorylation of AMPK and activation of peroxisome proliferator-activated receptor α, which influence the lipid and glucose metabolism of skeletal muscle and liver cells as well as inflammatory processes and vascular endothelial integrity. Several intracellular binding partners of the AdipoR N-terminus such as APPL1, CK2β and ERp46 have been identified and shown to control receptor signaling. Adiponectin has also been reported to modulate the dimerization and internalization of AdipoRs, which provides new insights into the molecular characteristics of this unusual receptor. The understanding of the functional mechanisms of adiponectin signal transduction is critical to benefit from the full therapeutic potential of the adiponectin-AdipoR system.

Fenofibrate inhibits intestinal Cl− secretion by blocking basolateral KCNQ1 K+ channels

2007 ◽  
Vol 293 (6) ◽  
pp. G1288-G1299 ◽  
Author(s):  
Poonam J. Bajwa ◽  
Abderrahmane Alioua ◽  
Jimmy W. Lee ◽  
Daniel S. Straus ◽  
Ligia Toro ◽  
...  
Keyword(s):  
Short Circuit ◽  
Ectopic Expression ◽  
Short Circuit Current ◽  
Selective Inhibition ◽  
Flux Analysis ◽  
Peroxisome Proliferator ◽  
Channel Activity ◽  
T84 Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Heat Stable

Fibrates are peroxisome proliferator-activated receptor-α (PPARα) ligands in widespread clinical use to lower plasma triglyceride levels. We investigated the effect of fenofibrate and clofibrate on ion transport in mouse intestine and in human T84 colonic adenocarcinoma cells through the use of short-circuit current ( Isc) and ion flux analysis. In mice, oral administration of fenofibrate produced a persistent inhibition of cAMP-stimulated electrogenic Cl− secretion by isolated jejunum and colon without affecting electroneutral fluxes of 22Na+ or 86Rb+ (K+) across unstimulated colonic mucosa. When applied acutely to isolated mouse intestinal mucosa, 100 μM fenofibrate inhibited cAMP-stimulated Isc within 5 min. In T84 cells, fenofibrate rapidly inhibited ∼80% the Cl− secretory responses to forskolin (cAMP) and to heat stable enterotoxin STa (cGMP) without affecting the response to carbachol (Ca2+). Both fenofibrate and clofibrate inhibited cAMP-stimulated Isc with an IC50 ∼1 μM, whereas other PPARα activators (gemfibrozil and Wy-14,643) were without effect. Membrane permeabilization experiments on T84 cells indicated that fenofibrate inhibits basolateral cAMP-stimulated K+ channels (putatively KCNQ1/KCNE3) without affecting Ca2+-stimulated K+ channel activity, whereas clofibrate inhibits both K+ pathways. Fenofibrate had no effect on apical cAMP-stimulated Cl− channel activity. Patch-clamp analysis of HEK-293T cells confirmed that 100 μM fenofibrate rapidly inhibits K+ currents associated with ectopic expression of human KCNQ1 with or without the KCNE3 β-subunit. We conclude that fenofibrate inhibits intestinal cAMP-stimulated Cl− secretion through a nongenomic mechanism that involves a selective inhibition of basolateral KCNQ1/KCNE3 channel complexes. Our findings raise the prospect of fenofibrate as a safe and effective antidiarrheal agent.

scholarly journals Inhibition of the Lipid Droplet–Peroxisome Proliferator-Activated Receptor α Axis Suppresses Cancer Stem Cell Properties

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 99
Author(s):  
Kenta Kuramoto ◽  
Masahiro Yamamoto ◽  
Shuhei Suzuki ◽  
Keita Togashi ◽  
Tomomi Sanomachi ◽  
...  
Keyword(s):  
Energy Source ◽  
Signal Transduction ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Peroxisome Proliferator ◽  
Cancer Stemness ◽  
Self Renewal ◽  
Peroxisome Proliferator Activated Receptor ◽  
Endogenous Lipid ◽  
Ppar Signaling

Cancer stem cells (CSCs), having both self-renewal and tumorigenic capacity, utilize an energy metabolism system different from that of non-CSCs. Lipid droplets (LDs) are organelles that store neutral lipids, including triacylglycerol. Previous studies demonstrated that LDs are formed and store lipids as an energy source in some CSCs. LDs play central roles not only in lipid storage, but also as a source of endogenous lipid ligands, which are involved in numerous signaling pathways, including the peroxisome proliferator-activated receptor (PPAR) signaling pathway. However, it remains unclear whether LD-derived signal transduction is involved in the maintenance of the properties of CSCs. We investigated the roles of LDs in cancer stemness using pancreatic and colorectal CSCs and isogenic non-CSCs. PPARα was activated in CSCs in which LDs accumulated, but not in non-CSCs, and pharmacological and genetic inhibition of PPARα suppressed cancer stemness. In addition, inhibition of both re-esterification and lipolysis pathways suppressed cancer stemness. Our study suggested that LD metabolic turnover accompanying PPARα activation is a promising anti-CSC therapeutic target.

scholarly journals Direct Binding of the Signal-transducing Adaptor Grb2 Facilitates Down-regulation of the Cyclin-dependent Kinase Inhibitor p27Kip1

2001 ◽  
Vol 276 (15) ◽  
pp. 12084-12090 ◽  
Author(s):  
Yoriko Sugiyama ◽  
Kiichiro Tomoda ◽  
Toshiaki Tanaka ◽  
Yukinobu Arata ◽  
Noriko Yoneda-Kato ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Kinase Inhibitor ◽  
Signal Sequence ◽  
Ectopic Expression ◽  
Signal Transduction Pathway ◽  
Transduction Pathway ◽  
Cyclin Dependent Kinase ◽  
Down Regulation ◽  
Cytoplasmic Transport ◽  
Subsequent Degradation

Ectopic expression of Jab1/CSN5 induces specific down-regulation of the cyclin-dependent kinase (Cdk) inhibitor p27 (p27Kip1) in a manner dependent upon transportation from the nucleus to the cytoplasm. Here we show that Grb2 and Grb3-3, the molecules functioning as an adaptor in the signal transduction pathway, specifically and directly bind to p27 in the cytoplasm and participate in the regulation of p27. The interaction requires the C-terminal SH3-domain of Grb2/3-3 and the proline-rich sequence contained in p27 immediately downstream of the Cdk binding domain. In living cells, enforcement of the cytoplasmic localization of p27, either by artificial manipulation of the nuclear/cytoplasmic transport signal sequence or by coexpression of ectopic Jab1/CSN5, markedly enhances the stable interaction between p27 and Grb2. Overexpression of Grb2 accelerates Jab1/CSN5-mediated degradation of p27, while Grb3-3 expression suppresses it. A p27 mutant unable to bind to Grb2 is transported into the cytoplasm in cells ectopically expressing Jab1/CSN5 but is refractory to the subsequent degradation. These findings indicate that Grb2 participates in a negative regulation of p27 and may directly link the signal transduction pathway with the cell cycle regulatory machinery.

scholarly journals Retinoic acid blocks adipogenesis by inhibiting C/EBPbeta-mediated transcription.

1997 ◽  
Vol 17 (3) ◽  
pp. 1552-1561 ◽  
Author(s):  
E J Schwarz ◽  
M J Reginato ◽  
D Shao ◽  
S L Krakow ◽  
M A Lazar
Keyword(s):  
Transcription Factors ◽  
Retinoic Acid ◽  
Transcriptional Activation ◽  
Adipocyte Differentiation ◽  
Ectopic Expression ◽  
Transient Transfection ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Necessary And Sufficient ◽  
Sequential Induction

Adipocyte differentiation is thought to involve sequential induction of the transcription factors C/EBPbeta, peroxisome proliferator-activated receptor gamma (PPARgamma), and C/EBPalpha. C/EBPalpha expression is both necessary and sufficient for adipocyte differentiation. Here we report that ectopic expression of either C/EBPalpha or C/EBPbeta induces PPARgamma expression and adipogenesis and that retinoic acid (RA) completely inhibits adipogenesis by either form of C/EBP. In studies of normal preadipocytes, RA does not prevent C/EBPbeta induction but blocks induction of PPARgamma, C/EBPalpha, and adipogenesis. In transient transfection studies, liganded RA receptor (RAR) specifically blocks transcriptional activation by either C/EBPalpha or C/EBPbeta. These results strongly suggest that C/EBPalpha substitutes for C/EBPbeta to induce adipocyte differentiation and that liganded RAR inhibits adipogenesis by blocking C/EBPbeta-mediated induction of downstream genes.

Peroxisome proliferators compete and ameliorate Hcy-mediated endocardial endothelial cell activation

2002 ◽  
Vol 283 (4) ◽  
pp. C1073-C1079 ◽  
Author(s):  
Matthew J. Hunt ◽  
Suresh C. Tyagi
Keyword(s):  
Fluorescence Quenching ◽  
Conformational Changes ◽  
Cell Activation ◽  
Intercellular Adhesion Molecule ◽  
Affinity Column ◽  
Peroxisome Proliferator ◽  
Endothelial Cell Activation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Dose Dependent

To determine whether homocysteine (Hcy)-mediated activation of endocardial endothelial (EE) cells is ameliorated by peroxisome proliferator-activated receptor (PPAR), we isolated EE cells from mouse endocardium. Matrix metalloproteinase (MMP) activity and intercellular adhesion molecule (ICAM)-1 in EE cells were measured in the presence and absence of Hcy, and ciprofibrate (CF; PPAR-α agonist) or 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2; PPAR-γ agonist) by zymography and Western blot analyses, respectively. Results suggest that Hcy-mediated MMP activation and ICAM-1 expression are ameliorated by CF and PGJ2. To test the hypothesis that Hcy competes with other ligands for binding to PPARα and -γ, we prepared cardiac nuclear extracts. Extracts were loaded onto an Hcy-cellulose affinity column. Bound proteins were eluted with CF and PGJ2. To determine conformational changes in PPAR upon binding to Hcy, we measured PPAR fluorescence at 334 nm. Dose-dependent increase in PPAR fluorescence demonstrated a primary binding affinity of 0.32 ± 0.06 μM. There was dose-dependent quenching of PPAR fluorescence by fluorescamine-homocysteine (F-Hcy). PPAR-α fluorescence quenching was abrogated by the addition of CF but not by PGJ2. PPAR-γ fluorescence quenching was abrogated by the addition of PGJ2 but not by CF. These results suggest that Hcy competes with CF and PGJ2 for binding to PPAR-α and -γ, respectively, indicating a role of PPAR in amelioration of Hcy-mediated EE dysfunction.

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