scholarly journals PPARγΔ5, a Naturally Occurring Dominant-Negative Splice Isoform, Impairs PPARγ Function and Adipocyte Differentiation

Cell Reports ◽  
2018 ◽  
Vol 25 (6) ◽  
pp. 1577-1592.e6 ◽  
Author(s):  
Marianna Aprile ◽  
Simona Cataldi ◽  
Maria Rosaria Ambrosio ◽  
Vittoria D’Esposito ◽  
Koini Lim ◽  
...  
Keyword(s):  
Adipocyte Differentiation ◽  
Dominant Negative ◽  
Naturally Occurring ◽  
Splice Isoform

scholarly journals Pref-1 Interacts with Fibronectin To Inhibit Adipocyte Differentiation

2010 ◽  
Vol 30 (14) ◽  
pp. 3480-3492 ◽  
Author(s):  
Yuhui Wang ◽  
Ling Zhao ◽  
Cynthia Smas ◽  
Hei Sook Sul
Keyword(s):  
Adipocyte Differentiation ◽  
Transmembrane Protein ◽  
Dominant Negative ◽  
Biologically Active ◽  
Mitogen Activated Protein Kinase ◽  
Soluble Form ◽  
Necrosis Factor Alpha ◽  
Rgd Peptides ◽  
Downstream Signaling ◽  
Erk Mapk

ABSTRACT Pref-1/Dlk1 is made as an epidermal growth factor (EGF) repeat-containing transmembrane protein but is cleaved by tumor necrosis factor alpha converting enzyme (TACE) to generate a biologically active soluble form. Soluble Pref-1 inhibits adipocyte differentiation through the activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) and the subsequent upregulation of Sox9 expression. However, others have implicated Notch in Pref-1 signaling and function. Here, we show that Pref-1 does not interact with, or require, Notch for its function. Instead, we show a direct interaction of Pref-1 and fibronectin via the Pref-1 juxtamembrane domain and fibronectin C-terminal domain. We also show that fibronectin is required for the Pref-1-mediated inhibition of adipocyte differentiation, the activation of ERK/MAPK, and the upregulation of Sox9. Furthermore, disrupting fibronectin binding to integrin by the addition of RGD peptides or by the knockdown of α5 integrin prevents the Pref-1 inhibition of adipocyte differentiation. Pref-1 activates the integrin downstream signaling molecules, FAK and Rac, and ERK activation by Pref-1 is blunted by the knockdown of Rac or by the forced expression of dominant-negative Rac. We conclude that, by interacting with fibronectin, Pref-1 activates integrin downstream signaling to activate MEK/ERK and to inhibit adipocyte differentiation.

scholarly journals The Naturally Occurring Variant of Estrogen Receptor (ER) ERΔE7 Suppresses Estrogen-Dependent Transcriptional Activation by Both Wild-Type ERα and ERβ

Endocrinology ◽  
2003 ◽  
Vol 144 (7) ◽  
pp. 2967-2976 ◽  
Author(s):  
Juana M. García Pedrero ◽  
Pedro Zuazua ◽  
Carlos Martínez-Campa ◽  
Pedro S. Lazo ◽  
Sofía Ramos
Keyword(s):  
Estrogen Receptor ◽  
Transcriptional Activation ◽  
Mammalian Cells ◽  
Activation Function ◽  
Inhibitory Effect ◽  
Dominant Negative ◽  
Wild Type ◽  
Independent Manner ◽  
Naturally Occurring ◽  
Estrogen Response

Abstract We have isolated and functionally characterized the exon 7-skipped variant (ERΔE7) of estrogen receptor (ER)α, which has emerged as the predominant variant expressed in multiple normal and tumoral tissues. However, to date no function has been established for this variant in mammalian cells. ERΔE7 exhibits a negligible ability to bind ligands, insensitivity to allosteric modulation by estrogen and antiestrogens, and loss of estrogen-dependent interaction with p160 coactivators such as SRC-1 and AIB1. ERΔE7 is able to form heterodimers with both ERα and ERβ in a ligand-independent manner. Transient expression experiments in HeLa cells show that increasing amounts of ERΔE7 result in a progressive inhibition of the estrogen-dependent transcriptional activation by both wild-type ERα and ERβ on estrogen response element-driven promoters. The inhibitory effect of ERΔE7 is due to the inhibition of binding of wild-type receptors to their responsive elements. Surprisingly, the activation function (AF)-1-dependent transactivation triggered by epithelial growth factor and phorbol-12-myristate-13-acetate is also abolished in ERΔE7 despite AF1 integrity, suggesting a cross-talk between AF1 and AF2 regions of the receptor. These results indicate that the naturally occurring variant ERΔE7 is a dominant negative receptor that, when expressed at high levels relative to wild-type ERs, might have profound effects on several estrogen-dependent functions.

scholarly journals A Naturally Occurring hPMS2 Mutation Can Confer a Dominant Negative Mutator Phenotype

1998 ◽  
Vol 18 (3) ◽  
pp. 1635-1641 ◽  
Author(s):  
Nicholas C. Nicolaides ◽  
Susan J. Littman ◽  
Paul Modrich ◽  
Kenneth W. Kinzler ◽  
Bert Vogelstein
Keyword(s):  
Mammalian Cells ◽  
Germ Line ◽  
Dominant Negative ◽  
Wild Type ◽  
Mutator Phenotype ◽  
Mmr Genes ◽  
Naturally Occurring ◽  
Hereditary Nonpolyposis ◽  
The Relationship ◽  
Present Experimental Evidence

ABSTRACT Defects in mismatch repair (MMR) genes result in a mutator phenotype by inducing microsatellite instability (MI), a characteristic of hereditary nonpolyposis colorectal cancers (HNPCC) and a subset of sporadic colon tumors. Present models describing the mechanism by which germ line mutations in MMR genes predispose kindreds to HNPCC suggest a “two-hit” inactivation of both alleles of a particular MMR gene. Here we present experimental evidence that a nonsense mutation at codon 134 of the hPMS2 gene is sufficient to reduce MMR and induce MI in cells containing a wild-type hPMS2 allele. These results have significant implications for understanding the relationship between mutagenesis and carcinogenesis and the ability to generate mammalian cells with mutator phenotypes.

scholarly journals ERBIN deficiency links STAT3 and TGF-β pathway defects with atopy in humans

2017 ◽  
Vol 214 (3) ◽  
pp. 669-680 ◽  
Author(s):  
J.J. Lyons ◽  
Y. Liu ◽  
C.A. Ma ◽  
X. Yu ◽  
M.P. O’Connell ◽  
...  
Keyword(s):  
Allergic Diseases ◽  
Foxp3 Expression ◽  
Receptor Activation ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Interacting Protein ◽  
Naturally Occurring ◽  
Pathway Activation

Nonimmunological connective tissue phenotypes in humans are common among some congenital and acquired allergic diseases. Several of these congenital disorders have been associated with either increased TGF-β activity or impaired STAT3 activation, suggesting that these pathways might intersect and that their disruption may contribute to atopy. In this study, we show that STAT3 negatively regulates TGF-β signaling via ERBB2-interacting protein (ERBIN), a SMAD anchor for receptor activation and SMAD2/3 binding protein. Individuals with dominant-negative STAT3 mutations (STAT3mut) or a loss-of-function mutation in ERBB2IP (ERBB2IPmut) have evidence of deregulated TGF-β signaling with increased regulatory T cells and total FOXP3 expression. These naturally occurring mutations, recapitulated in vitro, impair STAT3–ERBIN–SMAD2/3 complex formation and fail to constrain nuclear pSMAD2/3 in response to TGF-β. In turn, cell-intrinsic deregulation of TGF-β signaling is associated with increased functional IL-4Rα expression on naive lymphocytes and can induce expression and activation of the IL-4/IL-4Rα/GATA3 axis in vitro. These findings link increased TGF-β pathway activation in ERBB2IPmut and STAT3mut patient lymphocytes with increased T helper type 2 cytokine expression and elevated IgE.

Discovery of Naturally Occurring Splice Variants of the Rat Histamine H3Receptor That Act as Dominant-Negative Isoforms

2006 ◽  
Vol 69 (4) ◽  
pp. 1194-1206 ◽  
Author(s):  
Remko A. Bakker ◽  
Adrian Flores Lozada ◽  
André van Marle ◽  
Fiona C. Shenton ◽  
Guillaume Drutel ◽  
...  
Keyword(s):  
Splice Variants ◽  
Dominant Negative ◽  
Naturally Occurring

Dual suppression of adipogenesis by cigarette smoke through activation of the aryl hydrocarbon receptor and induction of endoplasmic reticulum stress

2009 ◽  
Vol 296 (4) ◽  
pp. E721-E730 ◽  
Author(s):  
Tsuyoshi Shimada ◽  
Nobuhiko Hiramatsu ◽  
Kunihiro Hayakawa ◽  
Shuhei Takahashi ◽  
Ayumi Kasai ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Aryl Hydrocarbon Receptor ◽  
Cigarette Smoke ◽  
Molecular Mechanisms ◽  
Adipocyte Differentiation ◽  
Suppressive Effect ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Aryl Hydrocarbon

Cigarette smoking decreases body weight, whereas molecular mechanisms underlying this phenomenon have not been elucidated. In this report, we investigated regulation of adipogenesis by cigarette smoke and involvement of aryl hydrocarbon receptor (AhR) and endoplasmic reticulum (ER) stress. We found that cigarette smoke extract (CSE) inhibited differentiation of preadipocytes into adipocytes dose dependently. It was associated with a decrease in lipid accumulation, blunted expression of adipocyte markers (adiponectin, PPAR-γ, and C/EBPα), and sustained expression of a preadipocyte marker MCP-1. CSE markedly induced activation of AhR, and AhR agonists (2,3,7,8-tetrachlorodibenzo- p-dioxin, benzo[ a]pyrene and 3-methylcholanthrene) reproduced the inhibitory effect of CSE on adipocyte differentiation. Furthermore, knockout of the AhR gene or blockade of AhR by a dominant-negative mutant attenuated the suppressive effects of CSE on adipocyte differentiation. We also found that CSE induced ER stress in preadipocytes, and ER stress inducers (thapsigargin, tunicamycin, and A23187) reproduced the suppressive effect of CSE on the differentiation of preadipocytes. Interestingly, AhR agonists did not cause ER stress, and ER stress inducers did not activate AhR. These results suggested that cigarette smoke has the potential to inhibit adipocyte differentiation via dual, independent mechanisms, i.e., through activation of the AhR pathway and induction of the unfolded protein response.

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