scholarly journals A Negative Regulatory Mechanism Involving 14-3-3ζ Limits Signaling Downstream of ROCK to Regulate Tissue Stiffness in Epidermal Homeostasis

2015 ◽  
Vol 35 (6) ◽  
pp. 759-774 ◽  
Author(s):  
Jasreen Kular ◽  
Kaitlin G. Scheer ◽  
Natasha T. Pyne ◽  
Amr H. Allam ◽  
Anthony N. Pollard ◽  
...  
Keyword(s):  
Regulatory Mechanism ◽  
Tissue Stiffness ◽  
Epidermal Homeostasis ◽  
Negative Regulatory Mechanism

scholarly journals Modulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Tao Yu ◽  
Shucheng Gan ◽  
Qingchen Zhu ◽  
Dongfang Dai ◽  
Ni Li ◽  
...  
Keyword(s):  
Immune Responses ◽  
Macrophage Activation ◽  
Regulatory Mechanism ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Creb Binding Protein ◽  
Human Macrophages ◽  
M2 Polarization ◽  
M2 Macrophage Polarization ◽  
Negative Regulatory Mechanism

Abstract Stat6 is known to drive macrophage M2 polarization. However, how macrophage polarization is fine-tuned by Stat6 is poorly understood. Here, we find that Lys383 of Stat6 is acetylated by the acetyltransferase CREB-binding protein (CBP) during macrophage activation to suppress macrophage M2 polarization. Mechanistically, Trim24, a CBP-associated E3 ligase, promotes Stat6 acetylation by catalyzing CBP ubiquitination at Lys119 to facilitate the recruitment of CBP to Stat6. Loss of Trim24 inhibits Stat6 acetylation and thus promotes M2 polarization in both mouse and human macrophages, potentially compromising antitumor immune responses. By contrast, Stat6 mediates the suppression of TRIM24 expression in M2 macrophages to contribute to the induction of an immunosuppressive tumor niche. Taken together, our findings establish Stat6 acetylation as an essential negative regulatory mechanism that curtails macrophage M2 polarization.

scholarly journals SAMHD1 Functions and Human Diseases

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 382 ◽  
Author(s):  
Si’Ana A. Coggins ◽  
Bijan Mahboubi ◽  
Raymond F. Schinazi ◽  
Baek Kim
Keyword(s):  
Cancer Biology ◽  
Genome Stability ◽  
Regulatory Mechanism ◽  
Cell Types ◽  
Interferon Signaling ◽  
Genomic Information ◽  
Viral Pathogens ◽  
Sam Domain ◽  
Deoxynucleoside Triphosphate ◽  
Negative Regulatory Mechanism

Deoxynucleoside triphosphate (dNTP) molecules are essential for the replication and maintenance of genomic information in both cells and a variety of viral pathogens. While the process of dNTP biosynthesis by cellular enzymes, such as ribonucleotide reductase (RNR) and thymidine kinase (TK), has been extensively investigated, a negative regulatory mechanism of dNTP pools was recently found to involve sterile alpha motif (SAM) domain and histidine-aspartate (HD) domain-containing protein 1, SAMHD1. When active, dNTP triphosphohydrolase activity of SAMHD1 degrades dNTPs into their 2′-deoxynucleoside (dN) and triphosphate subparts, steadily depleting intercellular dNTP pools. The differential expression levels and activation states of SAMHD1 in various cell types contributes to unique dNTP pools that either aid (i.e., dividing T cells) or restrict (i.e., nondividing macrophages) viral replication that consumes cellular dNTPs. Genetic mutations in SAMHD1 induce a rare inflammatory encephalopathy called Aicardi–Goutières syndrome (AGS), which phenotypically resembles viral infection. Recent publications have identified diverse roles for SAMHD1 in double-stranded break repair, genome stability, and the replication stress response through interferon signaling. Finally, a series of SAMHD1 mutations were also reported in various cancer cell types while why SAMHD1 is mutated in these cancer cells remains to investigated. Here, we reviewed a series of studies that have begun illuminating the highly diverse roles of SAMHD1 in virology, immunology, and cancer biology.

scholarly journals Genetic and Molecular Analysis of the Spm-dependent a-m2 Alleles of the Maize a Locus

Genetics ◽  
1987 ◽  
Vol 117 (1) ◽  
pp. 117-137
Author(s):  
Patrick Masson ◽  
Richard Surosky ◽  
Jeffrey A Kingsbury ◽  
Nina V Fedoroff
Keyword(s):  
Gene Expression ◽  
Transposable Element ◽  
Gene Product ◽  
Molecular Analysis ◽  
Regulatory Mechanism ◽  
Transposable Element Family ◽  
Genetic Organization ◽  
Derivatives Of ◽  
Negative Regulatory Mechanism ◽  
Insight Into

ABSTRACT The Suppressor-mutator (Spm) transposable element family of maize consists of the fully functional standard Spm (Spm-s) and many mutant elements. Insertion of an Spm element in or near a gene can markedly alter its expression, in some cases bringing the gene under the control of the mechanisms that regulate expression of the element. To gain insight into such mechanisms, as well as to enlarge our understanding of the Spm element's genetic organization, we have analyzed derivatives of a unique Spm insertion at the maize a locus in which the gene is co-expressed and co-regulated with the element. We describe the genetic properties and the structure of the a locus and Spm element in 9 strains (collectively designated the a-m2 alleles) selected by McClintock from the original a-m2 allele for heritable changes affecting either the Spm element or expression of the a gene. Most of the mutations are intra-element deletions within the 8.3-kb Spm element; many alter both Spm function and expression of the gene. Spm controls a gene expression in alleles with internally deleted, transposition-defective Spm elements and element ends contain the target sequences that mediate Spm's ability to activate expression of the gene. We argue that the properties of the a-m2 alleles reflect the operation of an element-encoded positive regulatory mechanism, as well as a negative regulatory mechanism that affects expression of the element, but appears not to be mediated by an element-encoded gene product.

scholarly journals Proteolytic Processing of Stat6 Signaling in Mast Cells as a Negative Regulatory Mechanism

2002 ◽  
Vol 196 (1) ◽  
pp. 27-38 ◽  
Author(s):  
Kotaro Suzuki ◽  
Hiroshi Nakajima ◽  
Shin-ichiro Kagami ◽  
Akira Suto ◽  
Kei Ikeda ◽  
...  
Keyword(s):  
Mast Cells ◽  
Regulatory Mechanism ◽  
Allergic Diseases ◽  
Proteolytic Processing ◽  
Dominant Negative ◽  
Negative Regulator ◽  
Nuclear Accumulation ◽  
Transactivation Domain ◽  
Negative Regulatory Mechanism

Accumulating evidence has shown the importance of Stat6-mediated signaling in allergic diseases. In this study, we show a novel regulatory mechanism of Stat6-mediated signaling in mast cells. When Stat6 is activated by interleukin (IL)-4 and translocated to the nucleus, Stat6 is cleaved by a nucleus-associated protease in mast cells. The cleaved 65-kD Stat6 lacks the COOH-terminal transactivation domain and functions as a dominant-negative molecule to Stat6-mediated transcription. The retrovirus-mediated expression of cleavage-resistant Stat6 mutants prolongs the nuclear accumulation of Stat6 upon IL-4 stimulation and enhances IL-4–induced gene expression and growth inhibition in mast cells. These results indicate that the proteolytic processing of Stat6 functions as a lineage-specific negative regulator of Stat6-dependent signaling in mast cells, and thus suggest that it may account for the limited role of Stat6 in IL-4 signaling in mast cells.

A secreted frizzled related protein, FrzA, selectively associates with Wnt-1 protein and regulates wnt-1 signaling

1999 ◽  
Vol 112 (21) ◽  
pp. 3815-3820 ◽  
Author(s):  
S. Dennis ◽  
M. Aikawa ◽  
W. Szeto ◽  
P.A. d'Amore ◽  
J. Papkoff
Keyword(s):  
Vascular Endothelium ◽  
Regulatory Mechanism ◽  
Beta Catenin ◽  
Related Protein ◽  
Biochemical Effect ◽  
Transmembrane Receptors ◽  
New Class ◽  
Wnt Proteins ◽  
Related Proteins ◽  
Negative Regulatory Mechanism

The Wnt gene family encodes proteins that serve key roles in differentiation and development. Wnt proteins interact with seven transmembrane receptors of the Frizzled family and activate a signaling pathway leading to the nucleus. A primary biochemical effect of Wnt-1 signaling is the stabilization of cytoplasmic (beta)-catenin which, in association with transcription factors of the Lef/tcf family, regulates gene expression. The recent identification of a new class of secreted proteins with similarity to the extracellular, ligand-binding domain of Frizzled proteins, soluble Frizzled related proteins (sFRP), suggested that additional mechanisms could regulate Wnt signaling. Here we demonstrate that FrzA, a sFRP that is highly expressed in vascular endothelium and a variety of epithelium, specifically binds to Wnt-1 protein, but not Wnt-5a protein, and modulates Wnt-1 signaling. FrzA associated with Wnt-1 either when expressed in the same cell or when soluble FrzA was incubated with Wnt-1-expressing cells. FrzA efficiently inhibited the Wnt-1 mediated increase in cytoplasmic (beta)-catenin levels as well as the Wnt-1 induction of transcription from a Lef/tcf reporter gene. The effects of FrzA on (beta)-catenin levels could be demonstrated when co-expressed with Wnt-1 or when individual cells expressing FrzA and Wnt-1 were co-cultured. These data demonstrate the existence of a negative regulatory mechanism mediated by the selective binding of FrzA to Wnt-1 protein.

scholarly journals ISM1 regulates NODAL signaling and asymmetric organ morphogenesis during development

2019 ◽  
Vol 218 (7) ◽  
pp. 2388-2402 ◽  
Author(s):  
Liliana Osório ◽  
Xuewei Wu ◽  
Linsheng Wang ◽  
Zhixin Jiang ◽  
Carlos Neideck ◽  
...  
Keyword(s):  
Regulatory Mechanism ◽  
Primitive Streak ◽  
Fine Tuning ◽  
Type I ◽  
Nodal Signaling ◽  
Biological Functions ◽  
Embryo Patterning ◽  
Left Right Asymmetry ◽  
Negative Regulatory Mechanism ◽  
Tgf Β1

Isthmin1 (ISM1) was originally identified as a fibroblast group factor expressed in Xenopus laevis embryonic brain, but its biological functions remain unclear. The spatiotemporal distribution of ISM1, with high expression in the anterior primitive streak of the chick embryo and the anterior mesendoderm of the mouse embryo, suggested that ISM1 may regulate signaling by the NODAL subfamily of TGB-β cytokines that control embryo patterning. We report that ISM1 is an inhibitor of NODAL signaling. ISM1 has little effect on TGF-β1, ACTIVIN-A, or BMP4 signaling but specifically inhibits NODAL-induced phosphorylation of SMAD2. In line with this observation, ectopic ISM1 causes defective left-right asymmetry and abnormal heart positioning in chick embryos. Mechanistically, ISM1 interacts with NODAL ligand and type I receptor ACVR1B through its AMOP domain, which compromises the NODAL–ACVR1B interaction and down-regulates phosphorylation of SMAD2. Therefore, we identify ISM1 as an extracellular antagonist of NODAL and reveal a negative regulatory mechanism that provides greater plasticity for the fine-tuning of NODAL signaling.

Sign in / Sign up

Export Citation Format

Share Document