scholarly journals Identification of BMP and Activin Membrane-Bound Inhibitor (BAMBI) as a Potent Negative Regulator of Adipogenesis and Modulator of Autocrine/Paracrine Adipogenic Factors

Diabetes ◽  
2011 ◽  
Vol 61 (1) ◽  
pp. 124-136 ◽  
Author(s):  
X. Luo ◽  
L. J. Hutley ◽  
J. A. Webster ◽  
Y.-H. Kim ◽  
D.-F. Liu ◽  
...  
Keyword(s):  
Negative Regulator ◽  
Membrane Bound ◽  
Potent Negative Regulator

scholarly journals NPHP4, a cilia-associated protein, negatively regulates the Hippo pathway

2011 ◽  
Vol 193 (4) ◽  
pp. 633-642 ◽  
Author(s):  
Sandra Habbig ◽  
Malte P. Bartram ◽  
Roman U. Müller ◽  
Ricarda Schwarz ◽  
Nikolaos Andriopoulos ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Nuclear Translocation ◽  
Hippo Pathway ◽  
Negative Regulator ◽  
Hippo Signaling ◽  
Transcriptional Coactivator ◽  
Hippo Signaling Pathway ◽  
The Hippo Pathway ◽  
Potent Negative Regulator

The conserved Hippo signaling pathway regulates organ size in Drosophila melanogaster and mammals and has an essential role in tumor suppression and the control of cell proliferation. Recent studies identified activators of Hippo signaling, but antagonists of the pathway have remained largely elusive. In this paper, we show that NPHP4, a known cilia-associated protein that is mutated in the severe degenerative renal disease nephronophthisis, acts as a potent negative regulator of mammalian Hippo signaling. NPHP4 directly interacted with the kinase Lats1 and inhibited Lats1-mediated phosphorylation of the Yes-associated protein (YAP) and TAZ (transcriptional coactivator with PDZ-binding domain), leading to derepression of these protooncogenic transcriptional regulators. Moreover, NPHP4 induced release from 14-3-3 binding and nuclear translocation of YAP and TAZ, promoting TEA domain (TEAD)/TAZ/YAP-dependent transcriptional activity. Consistent with these data, knockdown of NPHP4 negatively affected cellular proliferation and TEAD/TAZ activity, essentially phenocopying loss of TAZ function. These data identify NPHP4 as a negative regulator of the Hippo pathway and suggest that NPHP4 regulates cell proliferation through its effects on Hippo signaling.

Structure, function, and expression of SEL-1, a negative regulator of LIN-12 and GLP-1 in C. elegans

Development ◽  
1997 ◽  
Vol 124 (3) ◽  
pp. 637-644 ◽  
Author(s):  
B. Grant ◽  
I. Greenwald
Keyword(s):  
Staining Pattern ◽  
Signal Sequence ◽  
Negative Regulator ◽  
Yeast Gene ◽  
Hydrophobic Region ◽  
C Elegans ◽  
Cell Ablation ◽  
New Information ◽  
Membrane Bound ◽  
Punctate Staining

Previous work indicated that sel-1 functions as a negative regulator of lin-12 activity, and predicted that SEL-1 is a secreted or membrane associated protein. In this study, we describe cell ablation experiments that suggest sel-1 mutations elevate lin-12 activity cell autonomously. We also use transgenic approaches to demonstrate that the predicted signal sequence of SEL-1 can direct secretion and is important for function, while a C-terminal hydrophobic region is not required for SEL-1 function. In addition, by analyzing SEL-1 localization using specific antisera we find that SEL-1 is localized intracellularly, with a punctate staining pattern suggestive of membrane bound vesicles. We incorporate these observations, and new information about a related yeast gene, into a proposal for a possible mechanism for SEL-1 function in LIN-12 turnover.

scholarly journals USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Lei Ji ◽  
Bo Lu ◽  
Raffaella Zamponi ◽  
Olga Charlat ◽  
Robert Aversa ◽  
...  
Keyword(s):  
Osteoblast Differentiation ◽  
Adipocyte Differentiation ◽  
Ubiquitin Proteasome System ◽  
Cellular Systems ◽  
Negative Regulator ◽  
Scaffolding Protein ◽  
Complex Stability ◽  
Genetic Ablation ◽  
Ubiquitin Proteasome ◽  
Potent Negative Regulator

Abstract Axin is a key scaffolding protein responsible for the formation of the β-catenin destruction complex. Stability of Axin protein is regulated by the ubiquitin-proteasome system, and modulation of cellular concentration of Axin protein has a profound effect on Wnt/β-catenin signaling. Although E3s promoting Axin ubiquitination have been identified, the deubiquitinase responsible for Axin deubiquitination and stabilization remains unknown. Here, we identify USP7 as a potent negative regulator of Wnt/β-catenin signaling through CRISPR screens. Genetic ablation or pharmacological inhibition of USP7 robustly increases Wnt/β-catenin signaling in multiple cellular systems. USP7 directly interacts with Axin through its TRAF domain, and promotes deubiquitination and stabilization of Axin. Inhibition of USP7 regulates osteoblast differentiation and adipocyte differentiation through increasing Wnt/β-catenin signaling. Our study reveals a critical mechanism that prevents excessive degradation of Axin and identifies USP7 as a target for sensitizing cells to Wnt/β-catenin signaling.

Adenovirus-Mediated PD-L1 Over-Expression Has Differential Effects on Allograft Survival in Murine Islet and Heart Transplant Models.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4960-4960
Author(s):  
Wenda Gao ◽  
Kenichiro Yamashita ◽  
Jennifer Sullivan ◽  
Abraham Scaria ◽  
Terry B. Strom ◽  
...  
Keyword(s):  
Heart Transplant ◽  
Cell Activation ◽  
Fluorescent Protein ◽  
Negative Regulator ◽  
Allograft Survival ◽  
Over Expression ◽  
Gfp Gene ◽  
Membrane Bound ◽  
Transplant Model

Abstract Program death-1 (PD-1) is a negative regulator of the immune system. Blocking PD-1-mediated negative signaling accelerates autoimmune diseases, while engaging PD-1 with recombinant PD-L1Ig fusion protein potentiates the efficacy of co-stimulation blockade in prolonging allograft survival. However, soluble PD-L1Ig itself showed no graft-protecting effect, in contrast to its strong inhibition of T and B cell activation in vitro when applied in a plate-bound form. In this study, we tested the hypothesis that membrane-bound PD-L1 should prolong allograft survival due to its increased ability to crosslink PD-1 receptor. An adenovirus (Ad.PD-L1) was constructed to encode the full-length mPD-L1, followed by green fluorescent protein (GFP) gene linked by an IRES sequence. A control adenovirus (Ad.Ctrl) was similarly constructed that carries only the GFP gene. In islet transplant model, B6AF1 (H-2b/a) islets were infected with the adenoviruses, and then transplanted into C57BL/6 (H-2b) mice induced diabetic by streptozotocin. In heart transplant model, DBA/2 (H-2d) hearts were perfused with adenoviruses, and then transplanted into C57BL/6 mice. PD-L1 over-expression in islet did not prolong graft survival, but accelerated islet rejection (Ad.PD-L1: 9.0+/−3.5 days; Ad.Ctrl: 13.3+/−2.2 days). In contrast, infection with Ad.PD-L1 prolonged heart allograft survival (15.4+/−5.7 days) in C57BL/6 mice, which promptly rejected DBA/2 hearts (7.0+/−2.3 days, p<0.02). Thus, over-expression of membrane-bound PD-L1 has beneficial effect in an organ/tissue specific manner. Strategies other than direct expression of PD-L1 in the islet b cells need to be devised in order to utilize this negative pathway to prevent rejection.

scholarly journals Wall Tension Is a Potent Negative Regulator of In Vivo Thrombomodulin Expression

2003 ◽  
Vol 92 (1) ◽  
pp. 41-47 ◽  
Author(s):  
Jason L. Sperry ◽  
Clayton B. Deming ◽  
Ce Bian ◽  
Peter L. Walinsky ◽  
David A. Kass ◽  
...  
Keyword(s):  
Negative Regulator ◽  
Wall Tension ◽  
Potent Negative Regulator

Transforming Growth Factor-? Is a Potent Negative Regulator of Human Lymphocytes

1991 ◽  
Vol 628 (1 Negative Regu) ◽  
pp. 345-353 ◽  
Author(s):  
JOHN H. KEHRL ◽  
ALAN TAYLOR ◽  
SEONG-JIN KIM ◽  
ANTHONY S. FAUCI
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Human Lymphocytes ◽  
Negative Regulator ◽  
Potent Negative Regulator

scholarly journals A Novel Functional Screen in Human Cells Identifies MOCA as a Negative Regulator of Wnt Signaling

2008 ◽  
Vol 19 (11) ◽  
pp. 4660-4674 ◽  
Author(s):  
Elanite Caspi ◽  
Rina Rosin-Arbesfeld
Keyword(s):  
Cell Adhesion ◽  
Wnt Pathway ◽  
Target Genes ◽  
Negative Regulator ◽  
T Cell Factor ◽  
Functional Screen ◽  
Brain Cdna Library ◽  
Membrane Bound ◽  
Canonical Wnt ◽  
Wnt Signal

Aberrant Wnt signal transduction is involved in many human diseases such as cancer and neurodegenerative disorders. The key effector protein of the canonical Wnt pathway is β-catenin, which functions with T-cell factor/lymphoid enhancer factor (TCF/LEF) to activate gene transcription that leads to expression of Wnt target genes. In this study we provide results obtained from a novel functional screen of a human brain cDNA library used to identify 63 genes that are putative negative Wnt regulators. These genes were divided into eight functional groups that include known canonical and noncanonical Wnt pathway components and genes that had not yet been assigned to the Wnt pathway. One of the groups, the presenilin-binding proteins, contains the modifier of cell adhesion (MOCA) gene. We show that MOCA is a novel inhibitor of Wnt/β-catenin signaling. MOCA forms a complex with β-catenin and inhibits transcription of known Wnt target genes. Epistasis experiments indicate that MOCA acts to reduce the levels of nuclear β-catenin, increase the levels of membrane-bound β-catenin, and enhances cell–cell adhesion. Therefore, our data indicate that MOCA is a novel Wnt negative regulator and demonstrate that this screening approach can be a rapid means for isolation of new Wnt regulators.

scholarly journals Native KCC2 interactome reveals PACSIN1 as a critical regulator of synaptic inhibition

2017 ◽  
Author(s):  
Vivek Mahadevan ◽  
C. Sahara Khademullah ◽  
Zahra Dargaei ◽  
Jonah Chevrier ◽  
Pavel Uvarov ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Neurological Disorders ◽  
Hippocampal Neurons ◽  
Regulatory Protein ◽  
Reversal Potential ◽  
Negative Regulator ◽  
Excitatory Synapses ◽  
Receptor Recycling ◽  
Spine Morphogenesis ◽  
Potent Negative Regulator

AbstractKCC2 is a neuron-specific K+-Cl− cotransporter essential for establishing the Cl− gradient required for hyperpolarizing inhibition. KCC2 is highly localized to excitatory synapses where it regulates spine morphogenesis and AMPA receptor confinement. Aberrant KCC2 function contributes to numerous human neurological disorders including epilepsy and neuropathic pain. Using unbiased functional proteomics, we identified the KCC2-interactome in the mouse brain to determine KCC2-protein interactions that regulate KCC2 function. Our analysis revealed that KCC2 interacts with a diverse set of proteins, and its most predominant interactors play important roles in postsynaptic receptor recycling. The most abundant KCC2 interactor is a neuronal endocytic regulatory protein termed PACSIN1 (SYNDAPIN1). We verified the PACSIN1-KCC2 interaction biochemically and demonstrated that shRNA knockdown of PACSIN1 in hippocampal neurons significantly increases KCC2 expression and hyperpolarizes the reversal potential for Cl−. Overall, our global native-KCC2 interactome and subsequent characterization revealed PACSIN1 as a novel and potent negative regulator of KCC2.

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