scholarly journals Enzymatic insights into an inherited genetic disorder

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Liping Zhang ◽  
Kelly G Ten Hagen
Keyword(s):  
Protein Degradation ◽  
Signaling Pathway ◽  
Digestive Tract ◽  
Genetic Disorder

Mutations in an enzyme involved in protein degradation affect a signaling pathway that stimulates the development of the digestive tract.

scholarly journals Sea urchin larvae utilize light for regulating the pyloric opening

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Junko Yaguchi ◽  
Shunsuke Yaguchi
Keyword(s):  
Signaling Pathway ◽  
Digestive Tract ◽  
Sea Urchin ◽  
Visual Information ◽  
Biological Activities ◽  
Regulatory System ◽  
Sister Group ◽  
Animal Evolution ◽  
Deuterostome Evolution ◽  
Visual Systems

Abstract Background Light is essential for various biological activities. In particular, visual information through eyes or eyespots is very important for most of animals, and thus, the functions and developmental mechanisms of visual systems have been well studied to date. In addition, light-dependent non-visual systems expressing photoreceptor Opsins have been used to study the effects of light on diverse animal behaviors. However, it remains unclear how light-dependent systems were acquired and diversified during deuterostome evolution due to an almost complete lack of knowledge on the light-response signaling pathway in Ambulacraria, one of the major groups of deuterostomes and a sister group of chordates. Results Here, we show that sea urchin larvae utilize light for digestive tract activity. We found that photoirradiation of larvae induces pyloric opening even without addition of food stimuli. Micro-surgical and knockdown experiments revealed that this stimulating light is received and mediated by Go(/RGR)-Opsin (Opsin3.2 in sea urchin genomes) cells around the anterior neuroectoderm. Furthermore, we found that the anterior neuroectodermal serotoninergic neurons near Go-Opsin-expressing cells are essential for mediating light stimuli-induced nitric oxide (NO) release at the pylorus. Our results demonstrate that the light>Go-Opsin>serotonin>NO pathway functions in pyloric opening during larval stages. Conclusions The results shown here will lead us to understand how light-dependent systems of pyloric opening functioning via neurotransmitters were acquired and established during animal evolution. Based on the similarity of nervous system patterns and the gut proportions among Ambulacraria, we suggest the light>pyloric opening pathway may be conserved in the clade, although the light signaling pathway has so far not been reported in other members of the group. In light of brain-gut interactions previously found in vertebrates, we speculate that one primitive function of anterior neuroectodermal neurons (brain neurons) may have been to regulate the function of the digestive tract in the common ancestor of deuterostomes. Given that food consumption and nutrient absorption are essential for animals, the acquirement and development of brain-based sophisticated gut regulatory system might have been important for deuterostome evolution.

scholarly journals The role of Activin A in fibrodysplasia ossificans progressiva: a prominent mediator

2019 ◽  
Vol 39 (8) ◽  
Author(s):  
Hui Lin ◽  
Fuli Shi ◽  
Jiayu Gao ◽  
Ping Hua
Keyword(s):  
Signaling Pathway ◽  
Genetic Disorder ◽  
Activin A ◽  
Bmp Signaling ◽  
The Body ◽  
Fibrodysplasia Ossificans Progressiva ◽  
Type I ◽  
Heterotopic Bone ◽  
Heterotopic Bone Formation

Abstract Heterotopic ossification (HO) is the aberrant formation of mature, lamellar bone in nonosseous tissue. Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disorder that causes progressive HO in the ligaments, tendons, and muscles throughout the body. FOP is attributed to an autosomal mutation in activin receptor-like kinase 2 (ALK2), a bone morphogenetic protein (BMP) type I receptor. Initial studies show that mutant ALK2 drives HO by constitutively activating the BMP signaling pathway. Recently, mutant ALK2 has been shown to transduce Smad1/5 signaling and enhance chondrogenesis, calcification in response to Activin A, which normally signals through Smad2/3 and inhibits BMP signaling pathway. Furthermore, Activin A induces heterotopic bone formation via mutant ALK2, while inhibition of Activin A blocks spontaneous and trauma-induced HO. In this manuscript, we describe the molecular mechanism of the causative gene ALK2 in FOP, mainly focusing on the prominent role of Activin A in HO. It reveals a potential strategy for prevention and treatment of FOP by inhibition of Activin A. Further studies are needed to explore the cellular and molecular mechanisms of Activin A in FOP in more detail.

scholarly journals The DLC-1 tumor suppressor is involved in regulating immunomodulation of human mesenchymal stromal /stem cells through interacting with the Notch1 protein

2020 ◽  
Author(s):  
Tao Na ◽  
Kehua Zhang ◽  
Bao-Zhu Yuan
Keyword(s):  
Stem Cells ◽  
Tumor Suppressor ◽  
Protein Degradation ◽  
Signaling Pathway ◽  
Mutual Exclusion ◽  
Fine Tuning ◽  
Therapeutic Effects ◽  
Notch1 Signaling ◽  
Stromal Stem Cells ◽  
Immunomodulatory Function

Abstract BackgroundImmunomodulatory activities of human mesenchymal stromal /stem cells (hMSCs) has been widely recognized as the most critical function of hMSCs for exerting its therapeutic effects. However, the detailed mechanisms responsible for regulating the immunomodulation of hMSCs still remain largely unknown. Previous studies revealed that the Notch1 protein exerted a pro-immunomodulatory function probably through interacting with the protein(s) subjective to proteasome-mediated protein degradation. The DLC-1 protein represents a well characterized tumor suppressor subjective to proteasome-mediated degradation. However, the detailed signaling pathway of Notch1 and the involvement of DLC-1 in regulating the immunomodulation of hMSCs have not been studied before.MethodsThe transfection with cDNA or siRNA into hMSCs assisted by co-culture of hMSCs with peripheral blood mononuclear cells and small molecule inhibitors of signaling proteins, followed by immunoprecipitation, Western blotting, RT-PCR, and flowcytometry, were employed to characterize the Notch1 signaling, to identify DLC-1 as a candidate proteasome-targeted protein, and to characterize DLC-1 signaling pathway and its interaction with the Notch1 signaling, in the regulation of immunomodulation of hMSCs, specifically, the inhibition of pro-inflammatory CD4+-Th1 lymphocytes, and the release of immunomodulatory molecule IDO1.Statistical analysisOne-way ANOVA was utilized as a statistical tool to analyze the data presented as means ± SEM of at least three separate experiments.ResultsThe present study revealed that the Notch1-Hey1 axis, but not the Notch1-Hes1 axis, was likely responsible for mediating the pro-immunomodulatory function of the Notch1 signaling. The DLC-1 protein was found subjective to proteasome-mediated protein degradation mediated by the DDB1 and FBXW5 E3 ligases and served as an inhibitor of the immunomodulation of hMSCs through inhibiting Rock1, but not Rock2, downstream the DLC-1 signaling. The Notch1 signaling in the Notch1-Hey1 pathway and the DLC-1 signaling in the DLC-1-Rock1-FBXW5 pathway exhibited a mutual exclusion interaction in the regulation of immunomodulation of hMSCs.ConclusionsThe present study uncovers a novel function of DLC-1 tumor suppressor in regulating the immunomodulation of hMSCs. It also proposes a novel mutual exclusion mechanism between the DLC-1 signaling and the Notch1 signaling that is possibly responsible for fine-tuning the immunomodulation of hMSCs with different clinical implications in hMSCs therapy.

scholarly journals Histone H2A Nuclear/Cytoplasmic Trafficking Is Essential for Negative Regulation of Antiviral Immune Response and Lysosomal Degradation of TBK1 and IRF3

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao Man Wu ◽  
Hong Fang ◽  
Jie Zhang ◽  
Yong Hong Bi ◽  
Ming Xian Chang
Keyword(s):  
Immune Response ◽  
Protein Degradation ◽  
Signaling Pathway ◽  
Early Stage ◽  
Negative Regulation ◽  
Histone H2a ◽  
Antiviral Immune Response ◽  
Functional Complex ◽  
Host Innate Immune Response

Histone H2A is a nuclear molecule tightly associated in the form of the nucleosome. Our previous studies have demonstrated the antibacterial property of piscine H2A variants against gram-negative bacteria Edwardsiella piscicida and Gram-positive bacteria Streptococcus agalactiae. In this study, we show the function and mechanism of piscine H2A in the negative regulation of RLR signaling pathway and host innate immune response against spring viremia of carp virus (SVCV) infection. SVCV infection significantly inhibits the expression of histone H2A during an early stage of infection, but induces the expression of histone H2A during the late stage of infection such as at 48 and 72 hpi. Under normal physiological conditions, histone H2A is nuclear-localized. However, SVCV infection promotes the migration of histone H2A from the nucleus to the cytoplasm. The in vivo studies revealed that histone H2A overexpression led to the increased expression of SVCV gene and decreased survival rate. The overexpression of histone H2A also significantly impaired the expression levels of those genes involved in RLR antiviral signaling pathway. Furthermore, histone H2A targeted TBK1 and IRF3 to promote their protein degradation via the lysosomal pathway and impair the formation of TBK1-IRF3 functional complex. Importantly, histone H2A completely abolished TBK1-mediated antiviral activity and enormously impaired the protein expression of IRF3, especially nuclear IRF3. Further analysis demonstrated that the inhibition of histone H2A nuclear/cytoplasmic trafficking could relieve the protein degradation of TBK1 and IRF3, and blocked the negative regulation of histone H2A on the SVCV infection. Collectively, our results suggest that histone H2A nuclear/cytoplasmic trafficking is essential for negative regulation of RLR signaling pathway and antiviral immune response in response to SVCV infection.

scholarly journals Hereditary Hemorrhagic Telangiectasia: The ENT point of view

2020 ◽  
Vol 10 (37) ◽  
pp. 4-12
Author(s):  
Phillipe Eloy ◽  
Gabriela Musat
Keyword(s):  
Digestive Tract ◽  
20Th Century ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Genetic Disorder ◽  
Point Of View ◽  
Life Threatening ◽  
Vascular Dysplasia

AbstractHemorrhagic Hereditary Telangiectasia (HHT) disease, also called Osler-Weber-Rendu (OWR) disease, is a rare and underdiag-nosed genetic disorder characterized by a multisystemic vascular dysplasia. Nosebleeds, acute or chronic digestive tract bleeding and various problems due to the involvement of major organs (liver, lungs, brain) characterize the disease.Although it was described at the beginning of the 20th century, many patients, GPs and specialists still ignore the disease, its morbidities and the modalities of the treatment.That is the reason why the authors have decided to publish this review on this familiar, evolving and potentially life-threatening disease, whose management can be sometimes a real nightmare for the clinician.

scholarly journals The DLC-1 tumor suppressor is involved in regulating immunomodulation of human mesenchymal stem cells through interacting with the Notch1 protein

2020 ◽  
Author(s):  
Tao Na ◽  
Kehua Zhang ◽  
Bao-Zhu Yuan
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Tumor Suppressor ◽  
Protein Degradation ◽  
Signaling Pathway ◽  
Mutual Exclusion ◽  
Human Mesenchymal Stem Cells ◽  
Fine Tuning ◽  
Notch1 Signaling ◽  
Immunomodulatory Function

Abstract Background Immunomodulatory activities of human mesenchymal stem cells (hMSCs) has been widely recognized as the most critical function of hMSCs for exerting its therapeutic effects. However, the detailed mechanisms responsible for regulating the immunomodulation of hMSCs still remain largely unknown. Previous studies revealed that the Notch1 protein exerted a pro-immunomodulatory function probably through interacting with the protein(s) subjective to proteasome-mediated protein degradation. The DLC-1 protein represents a well characterized tumor suppressor subjective to proteasome-mediated degradation. However, the detailed signaling pathway of Notch1 and the involvement of DLC-1 in regulating the immunomodulation of hMSCs have not been studied before. Methods The transfection with cDNA or siRNA into hMSCs assisted by co-culture of hMSCs with peripheral blood mononuclear cells and small molecule inhibitors of signaling proteins, followed by immunoprecipitation, Western blotting, RT-PCR, and flowcytometry, were employed to characterize the Notch1 signaling, to identify DLC-1 as a candidate proteasome-targeted protein, and to characterize DLC-1 signaling pathway and its interaction with the Notch1 signaling, in the regulation of immunomodulation of hMSCs, specifically, the inhibition of pro-inflammatory CD4+-Th1 lymphocytes, and the release of immunomodulatory molecule IDO1. Statistical analysis One-way ANOVA was utilized as a statistical tool to analyze the data presented as means ± SEM of at least three separate experiments. Results The present study revealed that the Notch1-Hey1 axis, but not the Notch1-Hes1 axis, was likely responsible for mediating the pro-immunomodulatory function of the Notch1 signaling. The DLC-1 protein was found subjective to proteasome-mediated protein degradation mediated by the DDB1 and FBXW5 E3 ligases and served as an inhibitor of the immunomodulation of hMSCs through inhibiting Rock1, but not Rock2, downstream the DLC-1 signaling. The Notch1 signaling in the Notch1-Hey1 pathway and the DLC-1 signaling in the DLC-1-Rock1-FBXW5 pathway exhibited a mutual exclusion interaction in the regulation of immunomodulation of hMSCs. Conclusions The present study uncovers a novel function of DLC-1 tumor suppressor in regulating the immunomodulation of hMSCs. It also proposes a novel mutual exclusion mechanism between the DLC-1 signaling and the Notch1 signaling that is possibly responsible for fine-tuning the immunomodulation of hMSCs with different clinical implications in hMSCs therapy.

scholarly journals Senescence associated protein degradation

2017 ◽  
Author(s):  
Gerardo Ferbeyre
Keyword(s):  
Process Control ◽  
Protein Degradation ◽  
Signaling Pathway ◽  
Old Age ◽  
Ubiquitin Proteasome System ◽  
General Role ◽  
Cellular Processes ◽  
Ubiquitin Proteasome ◽  
Kinase Signaling Pathway ◽  
Map Kinase Signaling Pathway

AbstractSenescent cells accumulate with age and contribute to pathologies associated to old age. The senescent program can be induced by pro-cancer stimuli or is developmentally controlled. In cells forced to senesce by expression of oncogenes or short telomeres, aberrant activation of the ERK/MAP kinase signaling pathway leads to selective protein degradation by the ubiquitin proteasome system. The proteins affected by this process control key cellular processes known to be defective in senescent cells. We discuss the evidence supporting a general role for senescence associated protein degradation for organismal aging.

Transforming growth factor-beta signaling pathway in Marfan’s syndrome: a preliminary histopathological study

VASA ◽  
2011 ◽  
Vol 40 (5) ◽  
pp. 369-374 ◽  
Author(s):  
Yuan ◽  
Ma ◽  
Zhang ◽  
Jing
Keyword(s):  
Growth Factor ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Genetic Disorder ◽  
Elastic Fiber ◽  
Acid Mucopolysaccharide ◽  
Type I ◽  
Collagen Deposition ◽  
Tgf Beta ◽  
Hematoxylin Eosin

Background: Marfan’s syndrome is an inherited disorder that affects the connective tissue. It has been proposed that mutations of FBN1 gene or of transforming growth factor (TGF)-beta type II receptor may be responsible for its pathogenesis. However, the role of TGF-beta signaling pathway in the development of Marfan’s syndrome has not been comprehensively investigated. Materials and methods: Surgical specimens of the aorta were obtained from two female Marfan patients, and the control aortic tissue was taken from an autopsy of a healthy individual. The aortic specimens were examined with hematoxylin-eosin, Masson’s trichrome, von Gieson/victoria blue-van Gieson bichrome, and immunohistochemical stainings of TGF-beta1, TGF-beta type I receptor, Smad2/3, Smad4 and Smad7. Results: Hematoxylin-eosin staining demonstrated severe elastic lamellar disruption and patchy vascular smooth muscle dissolution in the aortic media of the Marfan patients. Collagen deposition, interlamilar elastic fiber fragmentation, loss or proliferation, and acid mucopolysaccharide accumulation were observed in the disarrayed aortic wall structures of Marfan patients by Masson’s trichrome, victoria blue-van Gieson bichrome, and Alcian blue and periodic schiff’s (AB-PAS) stainings, respectively. By immunohistochemistry, structural disruptions with enhanced TGF-beta;1 in the cytoplasm, Smad2/3 in the interstices, Smad4 in the cytoplasm, nuclei or interstices, and OOO Smad7, in the nucleus along with attenuated TGF-beta type I receptor in the aortic tissues of Marfan patients in comparison to the healthy control. Conclusions: Marfan patients may have aberrant TGF-beta signaling pathway associated with increased collagen deposition, interlamilar elastic fiber degenerative changes, and acid mucopolysaccharide accumulation. The signaling dysregulation may play an important role in the pathogenesis of this genetic disorder.

scholarly journals LINC00941 promotes CRC metastasis through preventing SMAD4 protein degradation and activating the TGF-β/SMAD2/3 signaling pathway

2020 ◽  
Vol 28 (1) ◽  
pp. 219-232 ◽  
Author(s):  
Nan Wu ◽  
Mingzuo Jiang ◽  
Haiming Liu ◽  
Yi Chu ◽  
Dan Wang ◽  
...  
Keyword(s):  
Protein Degradation ◽  
Signaling Pathway ◽  
Smad4 Protein
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