Xenopus nodal-related signaling is essential for mesendodermal patterning during early embryogenesis

Development ◽  
1999 ◽  
Vol 126 (14) ◽  
pp. 3229-3240 ◽  
Author(s):  
S.I. Osada ◽  
C.V. Wright
Keyword(s):  
Early Embryogenesis ◽  
Dominant Negative ◽  
Mesoderm Induction ◽  
Loss Of Function ◽  
Related Factors ◽  
Mutant Proteins ◽  
Organizer Activity ◽  
The Relationship ◽  
Protein Treatment ◽  
Transcript Induction

Previously, we showed that Xenopus nodal-related factors (Xnrs) can act as mesoderm inducers, and that activin induces Xnr transcription, suggesting that Xnrs relay or maintain induction processes initiated by activin-like molecules. We used a dominant negative cleavage mutant Xnr2 (cmXnr2) to carry out loss-of-function experiments to explore the requirement for Xnr signaling in early amphibian embryogenesis, and the relationship between activin and Xnrs. cmXnr2 blocked mesoderm induction caused by Xnr, but not activin, RNA. In contrast, cmXnr2 did suppress mesoderm and endoderm induction by activin protein, while Xnr transcript induction was unaffected by cmXnr2, consistent with an interference with the function of Xnr peptides that were induced by activin protein treatment. The severe hyperdorsalization and gastrulation defects caused by Xnr2 in whole embryos were rescued by cmXnr2, establishing a specific antagonistic relationship between the normal and cleavage mutant proteins. Expression of cmXnr2 resulted in delayed dorsal lip formation and a range of anterior truncations that were associated with delayed and suppressed expression of markers for dorsoanterior endoderm, in which the recently recognized head organizer activity resides. Reciprocally, Xnr2 induced dorsoanterior endodermal markers, such as cerberus, Xhex-1 and Frzb, in animal cap ectoderm. The migratory behavior of head mesendoderm explanted from cmXnr2 RNA-injected embryos was drastically reduced. These results indicate that Xnrs play crucial roles in initiating gastrulation, probably by acting downstream of an activin-like signaling pathway that leads to dorsal mesendodermal specification, including setting up the head organizer.

scholarly journals Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

2020 ◽  
Vol 217 (6) ◽  
Author(s):  
Vivien Béziat ◽  
Simon J. Tavernier ◽  
Yin-Huai Chen ◽  
Cindy S. Ma ◽  
Marie Materna ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Mutant Proteins ◽  
Skeletal Abnormalities ◽  
Tyrosine Residues ◽  
Hyper Ige Syndrome ◽  
Dominant Negative Mutations ◽  
Allergic Manifestations ◽  
Stat3 Mutations

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

scholarly journals Stat3 Activation Is Required for Cellular Transformation by v-src

1998 ◽  
Vol 18 (5) ◽  
pp. 2553-2558 ◽  
Author(s):  
Jacqueline F. Bromberg ◽  
Curt M. Horvath ◽  
Daniel Besser ◽  
Wyndham W. Lathem ◽  
James E. Darnell
Keyword(s):  
Cell Lines ◽  
Cellular Transformation ◽  
Human Tumors ◽  
Dominant Negative ◽  
Wild Type ◽  
Mutant Proteins ◽  
Transformed Cell ◽  
Transformed Cell Lines ◽  
Relationship Of ◽  
The Relationship

ABSTRACT Stat3 activation has been associated with cytokine-induced proliferation, anti-apoptosis, and transformation. Constitutively activated Stat3 has been found in many human tumors as well as v-abl- and v-src-transformed cell lines. Because of these correlations, we examined directly the relationship of activated Stat3 to cellular transformation and found that wild-type Stat3 enhances the transforming potential of v-src while three dominant negative Stat3 mutants inhibit v-srctransformation. Stat3 wild-type or mutant proteins did not affect v-ras transformation. We conclude that Stat3 has a necessary role in v-src transformation.

scholarly journals ALS/FTD mutations in UBQLN2 impede autophagy by reducing autophagosome acidification through loss of function

2020 ◽  
Vol 117 (26) ◽  
pp. 15230-15241 ◽  
Author(s):  
Josephine J. Wu ◽  
Ashley Cai ◽  
Jessie E. Greenslade ◽  
Nicole R. Higgins ◽  
Cong Fan ◽  
...  
Keyword(s):  
Hela Cells ◽  
Dominant Negative ◽  
Autophagic Flux ◽  
Loss Of Function ◽  
Mutant Proteins ◽  
Function Mechanism ◽  
Important Regulator ◽  
In Vitro Interaction ◽  
Lateral Sclerosis

Mutations inUBQLN2cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerations. However, the mechanism by which the UBQLN2 mutations cause disease remains unclear. Alterations in proteins involved in autophagy are prominent in neuronal tissue of human ALSUBQLN2patients and in a transgenic P497S UBQLN2 mouse model of ALS/FTD, suggesting a pathogenic link. Here, we show UBQLN2 functions in autophagy and that ALS/FTD mutant proteins compromise this function. Inactivation of UBQLN2 expression in HeLa cells reduced autophagic flux and autophagosome acidification. The defect in acidification was rescued by reexpression of wild type (WT) UBQLN2 but not by any of the five different UBQLN2 ALS/FTD mutants tested. Proteomic analysis and immunoblot studies revealed P497S mutant mice and UBQLN2 knockout HeLa and NSC34 cells have reduced expression of ATP6v1g1, a critical subunit of the vacuolar ATPase (V-ATPase) pump. Knockout of UBQLN2 expression in HeLa cells decreased turnover of ATP6v1g1, while overexpression of WT UBQLN2 increased biogenesis of ATP6v1g1 compared with P497S mutant UBQLN2 protein. In vitro interaction studies showed that ATP6v1g1 binds more strongly to WT UBQLN2 than to ALS/FTD mutant UBQLN2 proteins. Intriguingly, overexpression of ATP6v1g1 in UBQLN2 knockout HeLa cells increased autophagosome acidification, suggesting a therapeutic approach to overcome the acidification defect. Taken together, our findings suggest that UBQLN2 mutations drive pathogenesis through a dominant-negative loss-of-function mechanism in autophagy and that UBQLN2 functions as an important regulator of the expression and stability of ATP6v1g1. These findings may have important implications for devising therapies to treatUBQLN2-linked ALS/FTD.

Gfi1 as a Regulator of Hematopoietic Differentiation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-16-sci-16
Author(s):  
H. Leighton Grimes ◽  
Chinavenmeni S. Velu ◽  
Shane Horman ◽  
Aditya Chaubey ◽  
Tristan Bourdeau ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Target Genes ◽  
Cell Transformation ◽  
Bone Marrow Failure ◽  
Leukemia Virus ◽  
Dominant Negative ◽  
Insertion Mutagenesis ◽  
Loss Of Function ◽  
Mutant Proteins

Abstract Growth Factor Independent-1 (Gfi1) is a transcriptional repressor originally identified as a target of Moloney leukemia virus insertion mutagenesis. Gfi1 potently collaborates with Myc and Pim oncogenes to mediate T cell transformation. Retroviral insertions which activate Gfi1 are among the most frequent events in MoMLV-induced T cell, but not myeloid, leukemias. Orthologous proteins in Drosophila (Senseless) and C.elegans (Pag-3) are key regulators of developmental decisions. Gfi1−/− mice display lymphopenia, neutropenia, and abnormally proliferative HSC and progenitors which eventually lead to bone marrow failure. Humans with bone marrow failure syndromes, such as Severe Congenital Neutropenia or Non-Immune Chronic Idiopathic Neutropenia of Adults, display mutations in GFI1, which produce dominant negative acting GFI1 proteins. The SCN-associated GFI1N382S mutant proteins derepress a subset of GFI1 target genes, including CSF1 and CSF1R, to block granulopoeisis. Normally, Gfi1 antagonizes monopoiesis mediated by Pu.1, Egr1, Egr2, and Nab2. Thus, Gfi1 loss of function may impair granulopoiesis by failing to successfully repress monopoeitic differentiation. GFI1 dysfunction may also underlie Specific Granule Deficiency. GFI1 is able to synergize with C/EBP transcription factors to activate genes, such as neutrophil collagenase. Gfi1 may, therefore, enhance granulopoietic differentiation through C/EBP factors. Though great progress has been made in understanding Gfi1 biological and biochemical functions, we are only beginning to understand the role of Gfi1 in integrating hematopoietic transcriptional programming. We find that Gfi1 signaling controls both the differentiation and transformation of myeloid progenitors through an evolutionarily conserved transcriptional and post-transcriptional network.

scholarly journals A deep intronic splice mutation of STAT3 underlies hyper IgE syndrome by negative dominance

2019 ◽  
Vol 116 (33) ◽  
pp. 16463-16472 ◽  
Author(s):  
Joëlle Khourieh ◽  
Geetha Rao ◽  
Tanwir Habib ◽  
Danielle T. Avery ◽  
Alain Lefèvre-Utile ◽  
...  
Keyword(s):  
Dominant Negative ◽  
Loss Of Function ◽  
Wild Type ◽  
Dominant Form ◽  
Mutant Proteins ◽  
Coding Regions ◽  
Hyper Ige Syndrome ◽  
Autosomal Dominant Form ◽  
Negative Dominance ◽  
B And T Lymphocytes

Heterozygous in-frame mutations in coding regions of human STAT3 underlie the only known autosomal dominant form of hyper IgE syndrome (AD HIES). About 5% of familial cases remain unexplained. The mutant proteins are loss-of-function and dominant-negative when tested following overproduction in recipient cells. However, the production of mutant proteins has not been detected and quantified in the cells of heterozygous patients. We report a deep intronic heterozygous STAT3 mutation, c.1282-89C>T, in 7 relatives with AD HIES. This mutation creates a new exon in the STAT3 complementary DNA, which, when overexpressed, generates a mutant STAT3 protein (D427ins17) that is loss-of-function and dominant-negative in terms of tyrosine phosphorylation, DNA binding, and transcriptional activity. In immortalized B cells from these patients, the D427ins17 protein was 2 kDa larger and 4-fold less abundant than wild-type STAT3, on mass spectrometry. The patients’ primary B and T lymphocytes responded poorly to STAT3-dependent cytokines. These findings are reminiscent of the impaired responses of leukocytes from other patients with AD HIES due to typical STAT3 coding mutations, providing further evidence for the dominance of the mutant intronic allele. These findings highlight the importance of sequencing STAT3 introns in patients with HIES without candidate variants in coding regions and essential splice sites. They also show that AD HIES-causing STAT3 mutant alleles can be dominant-negative even if the encoded protein is produced in significantly smaller amounts than wild-type STAT3.

scholarly journals Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome

2021 ◽  
Author(s):  
Stephanie C. Harrison ◽  
Christo Tsilifis ◽  
Mary A. Slatter ◽  
Zohreh Nademi ◽  
Austen Worth ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Early Report ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
Hyper Ige Syndrome

AbstractAutosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor TH17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.

scholarly journals Relationship between Social Skills and Happiness: Differences by Gender

2021 ◽  
Vol 18 (15) ◽  
pp. 7929
Author(s):  
Carlos Salavera ◽  
Pablo Usán
Keyword(s):  
Gender Differences ◽  
Social Skills ◽  
Social Interactions ◽  
Primary Education ◽  
Subjective Happiness ◽  
School Students ◽  
Related Factors ◽  
Subjective Happiness Scale ◽  
Social Settings ◽  
The Relationship

This study examines the relationship between social skills and happiness in 1st-year Teaching School students, as well as possible gender differences. The sample comprised 243 Teaching School students (Primary Education) in Zaragoza, including 110 men (45.27%) and 133 women (54.73%), aged 18–25 (average age 20.23 years; s.d. = 1.586). In order to analyse the relationship between social skills and subjective happiness, the Scale of Social Skills and Subjective Happiness Scale were used. While men scored higher in all social skills-related factors, women scored higher in all factors related to happiness. The study shows that factors such as self-expression in social settings and the ability to say no and cut off social interactions have a direct and significant effect on happiness among men, while self-expression in social settings and the ability to express anger led to a higher perception of happiness among women. Similarly, situations such as asking for and defending rights have an indirect and significant effect in men, reducing their levels of happiness. In the case of women, no social skills factors were found that led to lower happiness. It may be concluded that significant gender differences exist, although broader and lateral studies are needed in order to examine the relationship between gender identities, social skills and subjective happiness more in depth, and thus, understand the effect of these constructs in the development of personality.

scholarly journals Mutation-specific non-canonical pathway of PTEN as a distinct therapeutic target for glioblastoma

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Seung Won Choi ◽  
Yeri Lee ◽  
Kayoung Shin ◽  
Harim Koo ◽  
Donggeon Kim ◽  
...  
Keyword(s):  
Functional Properties ◽  
Therapeutic Target ◽  
Medical Center ◽  
Dominant Negative ◽  
The Cancer Genome Atlas ◽  
Dominant Negative Effect ◽  
Cell Periphery ◽  
Missense Mutations ◽  
Phosphatase Domain ◽  
Mutant Proteins

AbstractPTEN is one of the most frequently altered tumor suppressor genes in malignant tumors. The dominant-negative effect of PTEN alteration suggests that the aberrant function of PTEN mutation might be more disastrous than deletion, the most frequent genomic event in glioblastoma (GBM). This study aimed to understand the functional properties of various PTEN missense mutations and to investigate their clinical relevance. The genomic landscape of PTEN alteration was analyzed using the Samsung Medical Center GBM cohort and validated via The Cancer Genome Atlas dataset. Several hotspot mutations were identified, and their subcellular distributions and phenotypes were evaluated. We established a library of cancer cell lines that overexpress these mutant proteins using the U87MG and patient-derived cell models lacking functional PTEN. PTEN mutations were categorized into two major subsets: missense mutations in the phosphatase domain and truncal mutations in the C2 domain. We determined the subcellular compartmentalization of four mutant proteins (H93Y, C124S, R130Q, and R173C) from the former group and found that they had distinct localizations; those associated with invasive phenotypes (‘edge mutations’) localized to the cell periphery, while the R173C mutant localized to the nucleus. Invasive phenotypes derived from edge substitutions were unaffected by an anti-PI3K/Akt agent but were disrupted by microtubule inhibitors. PTEN mutations exhibit distinct functional properties regarding their subcellular localization. Further, some missense mutations (‘edge mutations’) in the phosphatase domain caused enhanced invasiveness associated with dysfunctional cytoskeletal assembly, thus suggesting it to be a potent therapeutic target.

scholarly journals A Modified Screening System for Loss-of-Function and Dominant Negative Alleles of Essential MCMV Genes

PLoS ONE ◽  
2014 ◽  
Vol 9 (4) ◽  
pp. e94918
Author(s):  
Madlen Pogoda ◽  
Jens B. Bosse ◽  
Karl-Klaus Conzelmann ◽  
Ulrich H. Koszinowski ◽  
Zsolt Ruzsics
Keyword(s):  
Dominant Negative ◽  
Screening System ◽  
Loss Of Function

scholarly journals Exploring Employment Trend and Relationship With Individual and Family-Related Factors in 65 or Older Koreans

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 65-65
Author(s):  
Yeonji Ryou ◽  
Ryou Yeonji
Keyword(s):  
Employment Status ◽  
Secondary Data ◽  
Educational Background ◽  
Health Condition ◽  
Related Factors ◽  
The People ◽  
Close Relationship ◽  
Working People ◽  
The Status ◽  
The Relationship

Abstract The purpose of this study is to identify the trend of the employment status in 65 years or older adults who reside in South Korea and to explore the relationship between the status of employment and individual and family-related factors. This study utilized 10-year and 6-wave secondary data from the Korean Longitudinal Study of Ageing (KLoSA). The original panel sample is a random sample of 10,254 adults who are 45 or older, but for the aim of this study, the participants younger than 65 years were excluded. The number of samples in each wave is different, ranging from 4,013 to 4,335 due to the death of the participant, the rejection of additional interviews, and the refreshment participant collected in Wave 5. The findings indicate that the absolute employment of the people aged 65 or older and the proportion of working people among those have increased over the past decade. In this study, it is also found that there is a close relationship between employment status and individual factors such as gender, educational background, health condition, region, etc. Moreover, the results suggest that there are various facets of the relationship between employment status and family-related factors including whether living with children, the number of the member whom I help with daily activities, the total amount of financial support from/to children/parents/other family or whether participating social activities, etc. The implications of the need for employing the older population and the consideration family-related factors in the policy-making process in Korea are discussed.

Sign in / Sign up

Export Citation Format

Share Document