Kel1 is a phosphorylation-regulated noise suppressor of the pheromone signaling pathway

Mechanisms have evolved that allow cells to detect signals and generate an appropriate response. The accuracy of these responses relies on the ability of cells to discriminate between signal and noise. How cells filter noise in signaling pathways is not well understood. We have analyzed noise suppression in the yeast pheromone signaling pathway. By combining synthetic genetic array screening, mass spectrometry and single-cell time-resolved microscopy, we discovered that the poorly characterized protein Kel1 serves as a major noise suppressor of the pathway. At the molecular level, Kel1 suppresses spontaneous activation of the pheromone response by inhibiting membrane recruitment of Ste5 and Far1. Kel1 is regulated by phosphorylation, and only the hypophosphorylated form of Kel1 suppresses signaling, reduces noise and prevents pheromone-associated cell death. Our data indicate that in response to pheromone the MAPKs Fus3 and Kss1 phosphorylate Kel1 to relieve inhibition of the pheromone pathway. Taken together, Kel1 serves as a phospho-regulated suppressor of the pheromone pathway to reduce noise, inhibit spontaneous activation of the pathway, regulate mating efficiency and to prevent pheromone-associated cell death.

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Faculty Opinions recommendation of Nitrate efflux is an essential component of the cryptogein signaling pathway leading to defense responses and hypersensitive cell death in tobacco.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1011782.182572 ◽

2003 ◽

Author(s):

Eric Lam

Keyword(s):

Cell Death ◽

Signaling Pathway ◽

Defense Responses ◽

Hypersensitive Cell Death ◽

Essential Component

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Mot3, a Zn Finger Transcription Factor That Modulates Gene Expression and Attenuates Mating Pheromone Signaling in Saccharomyces cerevisiae

Genetics ◽

10.1093/genetics/149.2.879 ◽

1998 ◽

Vol 149 (2) ◽

pp. 879-892 ◽

Cited By ~ 1

Author(s):

Anatoly V Grishin ◽

Michael Rothenberg ◽

Maureen A Downs ◽

Kendall J Blumer

Keyword(s):

Gene Expression ◽

Saccharomyces Cerevisiae ◽

Signaling Pathway ◽

G Protein ◽

Binding Sites ◽

Dependent Manner ◽

Pheromone Response ◽

Mating Pheromone ◽

Pheromone Signaling ◽

Yeast Genes

Abstract In the yeast Saccharomyces cerevisiae, mating pheromone response is initiated by activation of a G protein- and mitogen-activated protein (MAP) kinase-dependent signaling pathway and attenuated by several mechanisms that promote adaptation or desensitization. To identify genes whose products negatively regulate pheromone signaling, we screened for mutations that suppress the hyperadaptive phenotype of wild-type cells overexpressing signaling-defective G protein β subunits. This identified recessive mutations in MOT3, which encodes a nuclear protein with two Cys2-His2 Zn fingers. MOT3 was found to be a dosage-dependent inhibitor of pheromone response and pheromone-induced gene expression and to require an intact signaling pathway to exert its effects. Several results suggested that Mot3 attenuates expression of pheromone-responsive genes by mechanisms distinct from those used by the negative transcriptional regulators Cdc36, Cdc39, and Mot2. First, a Mot3-lexA fusion functions as a transcriptional activator. Second, Mot3 is a dose-dependent activator of several genes unrelated to pheromone response, including CYC1, SUC2, and LEU2. Third, insertion of consensus Mot3 binding sites (C/A/T)AGG(T/C)A activates a promoter in a MOT3-dependent manner. These findings, and the fact that consensus binding sites are found in the 5′ flanking regions of many yeast genes, suggest that Mot3 is a globally acting transcriptional regulator. We hypothesize that Mot3 regulates expression of factors that attenuate signaling by the pheromone response pathway.

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Eriodictyol protects against H2O2-induced neuron-like PC12 cell death through activation of Nrf2/ARE signaling pathway

Neurochemistry International ◽

10.1016/j.neuint.2012.05.013 ◽

2012 ◽

Vol 61 (2) ◽

pp. 251-257 ◽

Cited By ~ 42

Author(s):

Haiyan Lou ◽

Xu Jing ◽

Dongmei Ren ◽

Xinbing Wei ◽

Xiumei Zhang

Keyword(s):

Cell Death ◽

Signaling Pathway ◽

Pc12 Cell ◽

Induced Neuron

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v-CRK, AN EFFECTOR OF THE NERVE GROWTH FACTOR SIGNALING PATHWAY, DELAYS APOPTOTIC CELL DEATH IN NEUROTROPHIN-DEPRIVED PC12 CELLS

Biochemical Society Transactions ◽

10.1042/bst024573sb ◽

1996 ◽

Vol 24 (4) ◽

pp. 573S-573S

Author(s):

Robert H. Glassman ◽

Barbara L. Hempstead ◽

Hidesaburo Hanafusa ◽

Raymond B. Birge

Keyword(s):

Cell Death ◽

Nerve Growth Factor ◽

Growth Factor ◽

Signaling Pathway ◽

Pc12 Cells ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Growth Factor Signaling ◽

Nerve Growth ◽

Growth Factor Signaling Pathway

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Age-associated features of the expression level of apoptosis markers in cardiomyocytes of patients with dilated cardiomyopathy

Успехи геронтологии ◽

10.34922/ae.2021.34.6.010 ◽

2022 ◽

pp. 885-890

Author(s):

К.П. Кравченко ◽

К. Л. Козлов ◽

А.О. Дробинцева ◽

Д.С. Медведев ◽

В.О. Полякова

Keyword(s):

Cell Death ◽

Dilated Cardiomyopathy ◽

Molecular Mechanisms ◽

Molecular Level ◽

Confocal Laser ◽

Control Group ◽

Cellular Mechanisms ◽

Apoptosis Pathway ◽

Bax Protein

Для понимания патогенеза дилатационной кардиомиопатии (ДКМП) необходимо установить молекулярно-клеточные механизмы старения миокарда, в том числе связанные с программируемой клеточной гибелью, молекулярные механизмы которого практически не изучены. Цель работы - изучение маркеров апоптоза в кардиомиоцитах у пациентов с ДКМП in vitro. В работе использовали метод первичных диссоциированных клеточных культур и метод иммунофлюоресцентной конфокальной лазерной микроскопии. Для моделирования клеточного старения использовали клетки 3-го и 14-го пассажей, соответствующие «молодым» и «старым» культурам. На молекулярном уровне старение клеток кардиомиоцитов сопровождалось повышением экспрессии р16 в 2 раза по сравнению с «молодыми культурами» как в контрольной, так и в группе с ДКМП. Также установлено, что экспрессия р16 в культурах, взятых от пациентов с патологией, была в 2 раза выше, чем в аналогичных культурах от здоровых пациентов. Экспрессия р21 была повышена в группе с ДКМП по сравнению с контрольной группой, однако при старении культуры экспрессия p21 не изменялась, оставаясь на высоком уровне. Наиболее значимые различия были получены при сравнении экспрессии Bax в культуре клеток кардиомиоцитов из группы с ДКМП в «молодой» культуре с нормой - в 3,2 раза. Старение клеток миокарда на молекулярном уровне проявлялось в повышении экспрессии белка Baх, именно он является запускающим механизмом митохондриального пути апоптоза. Возможно, этот путь клеточной гибели является превалирующем при ДКМП. To understand the pathogenesis of dilated cardiomyopathy (DCMP), it is necessary to establish the molecular-cellular mechanisms of myocardial aging, including those associated with programmed cell death, the molecular mechanisms of which have not been practically studied. The aim of this work is to study markers of apoptosis in cardiomyocytes of patients with DCMP in vitro. We used the method of primary dissociated cell cultures and the method of immunofluorescence confocal laser microscopy. Cells of the 3 and 14 passages, corresponding to «young» and «old» cultures, were used to simulate cellular senescence. Results. At the molecular level, aging of cardiomyocyte cells was accompanied by a twofold increase in the expression of p16 compared to «young cultures» both in the control group and in the group with DCMP. It was also found that the expression of p16 in cultures taken from patients with pathology was 2 times higher than in similar cultures from healthy patients. The expression of p21 was increased in the group with DCMP compared to the control; however, with aging of the culture, the expression of p21 did not change, remaining at a significant level. The most significant differences were obtained when comparing the expression of Bax in the cell culture of cardiomyocytes from the group with DCMP in a «young» culture compared with the norm, 3,2 times. Aging of myocardial cells at the molecular level was manifested in an increase in the expression of the Bax protein, which is the triggering mechanism of the mitochondrial apoptosis pathway. It is possible that this pathway of cell death is prevalent in DCMP.

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Neuroprotection after Hemorrhagic Stroke Depends on Cerebral Heme Oxygenase-1

Antioxidants ◽

10.3390/antiox8100496 ◽

2019 ◽

Vol 8 (10) ◽

pp. 496 ◽

Cited By ~ 3

Author(s):

Sandra Kaiser ◽

Sibylle Frase ◽

Lisa Selzner ◽

Judith-Lisa Lieberum ◽

Jakob Wollborn ◽

...

Keyword(s):

Cell Death ◽

Cerebrospinal Fluid ◽

Functional Outcome ◽

Signaling Pathway ◽

Heme Oxygenase ◽

Hemorrhagic Stroke ◽

Mrna Level ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Heme Oxygenase 1

(1) Background: A detailed understanding of the pathophysiology of hemorrhagic stroke is still missing. We hypothesized that expression of heme oxygenase-1 (HO-1) in microglia functions as a protective signaling pathway. (2) Methods: Hippocampal HT22 neuronal cells were exposed to heme-containing blood components and cell death was determined. We evaluated HO-1-induction and cytokine release by wildtype compared to tissue-specific HO-1-deficient (LyzM-Cre.Hmox1 fl/fl) primary microglia (PMG). In a study involving 46 patients with subarachnoid hemorrhage (SAH), relative HO-1 mRNA level in the cerebrospinal fluid were correlated with hematoma size and functional outcome. (3) Results: Neuronal cell death was induced by exposure to whole blood and hemoglobin. HO-1 was induced in microglia following blood exposure. Neuronal cells were protected from cell death by microglia cell medium conditioned with blood. This was associated with a HO-1-dependent increase in monocyte chemotactic protein-1 (MCP-1) production. HO-1 mRNA level in the cerebrospinal fluid of SAH-patients correlated positively with hematoma size. High HO-1 mRNA level in relation to hematoma size were associated with improved functional outcome at hospital discharge. (4) Conclusions: Microglial HO-1 induction with endogenous CO production functions as a crucial signaling pathway in blood-induced inflammation, determining microglial MCP-1 production and the extent of neuronal cell death. These results give further insight into the pathophysiology of neuronal damage after SAH and the function of HO-1 in humans.

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Nitrate Efflux Is an Essential Component of the Cryptogein Signaling Pathway Leading to Defense Responses and Hypersensitive Cell Death in Tobacco

The Plant Cell ◽

10.1105/tpc.002295 ◽

2002 ◽

Vol 14 (8) ◽

pp. 1937-1951 ◽

Cited By ~ 95

Author(s):

David Wendehenne ◽

Olivier Lamotte ◽

Jean-Marie Frachisse ◽

Hélène Barbier-Brygoo ◽

Alain Pugin

Keyword(s):

Cell Death ◽

Signaling Pathway ◽

Defense Responses ◽

Hypersensitive Cell Death ◽

Essential Component

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Sequence Analysis and Homology Modeling of NF2 Protein

International Journal of Scientific Research in Science and Technology ◽

10.32628/ijsrst196159 ◽

2019 ◽

pp. 373-377

Author(s):

Vinod P. Sinoorkar ◽

Pratiksha S. Thakurdas

Keyword(s):

Cell Death ◽

Signaling Pathway ◽

Actin Binding ◽

Hippo Signaling ◽

Β Cell ◽

Neurofibromatosis 2 ◽

Pancreatic Cell ◽

Hippo Signaling Pathway ◽

Molecular Features ◽

Chronic Hyperglycemia

Diabetes is diseases characterized by chronic hyperglycemia resulting from defects in insulin secretion, insulin action, or both. In India more than 62 million individuals currently diagnosed with the diabetes. Diabetes is resulting from insulin deficiency or pancreatic cells become insulin resistant. Pancreatic cell (β-cell) death by apoptosis is one of main reason which results in diabetic condition in patients. Neurofibromatosis 2 is involved is β-cell death. Neurofibromatosis 2 (NF2/Merlin) is a tumor suppressor protein, which belongs to the ezrin–radixin–moesin family of actin-binding proteins and regulates the Hippo signaling pathway in mammals and also involved in the regulation of cell proliferation and apoptosis. Merlin regulates the Hippo signaling pathway by controlling the Hippo kinases cassettes MST1/2 and LATS1/2. Therefore, targeting β-cell apoptosis and dysfunction can be a therapeutic approach for the treatment of diabetes. Hence our present investigation focus mainly to understand the detailed molecular features of NF2 by its protein sequence annotation by implementing tools and techniques of Bioinformatics.

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ZBP1 induces inflammatory signaling via RIPK3 and promotes SARS-CoV-2-induced cytokine expression

10.1101/2021.10.01.462460 ◽

2021 ◽

Author(s):

Ruoshi Peng ◽

Xuan Wang-Kan ◽

Manja Idorn ◽

Felix Y Zhou ◽

Susana L Orozco ◽

...

Keyword(s):

Cell Death ◽

Signaling Pathway ◽

Kinase Activity ◽

Caspase 8 ◽

Dependent Manner ◽

Innate Immune Responses ◽

Inflammatory Signaling ◽

Antiviral Responses ◽

Nucleic Acid Sensor ◽

Activity Dependent

AbstractCOVID-19 caused by the SARS-CoV-2 virus remains a threat to global health. The disease severity is mediated by cell death and inflammation, which regulate both the antiviral and the pathological innate immune responses. ZBP1, an interferon-induced cytosolic nucleic acid sensor, facilitates antiviral responses via RIPK3. Although ZBP1-mediated cell death is widely described, whether and how it promotes inflammatory signaling is unclear. Here, we report a ZBP1-induced inflammatory signaling pathway that depends on ubiquitination and RIPK3’s scaffolding ability independently of cell death. In human cells, ZBP1 associates with RIPK1 and RIPK3 as well as ubiquitin ligases cIAP1 and LUBAC. RIPK1 and ZBP1 are ubiquitinated to promote TAK1- and IKK-mediated inflammatory signaling. Additionally, RIPK1 recruits the p43/41-caspase-8-p43-FLIP heterodimer to suppress RIPK3 kinase activity, which otherwise promotes inflammatory signaling in a kinase activity-dependent manner. Lastly, we show that ZBP1 contributes to SARS-CoV-2-induced cytokine production. Taken together, we describe a ZBP1-RIPK1-RIPK3-mediated inflammatory signaling pathway relayed by the scaffolding role of RIPKs and regulated by caspase-8. Our results suggest the ZBP1 pathway contributes to inflammation in response to SARS-CoV-2 infection.

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