Vinexin contributes to autophagic decline in brain ageing across species

AbstractAutophagic decline is considered a hallmark of ageing. The activity of this intracytoplasmic degradation pathway decreases with age in many tissues and autophagy induction ameliorates ageing in many organisms, including mice. Autophagy is a critical protective pathway in neurons and ageing is the primary risk factor for common neurodegenerative diseases. Here, we describe that autophagosome biogenesis declines with age in mouse brains and that this correlates with increased expression of the SORBS3 gene (encoding vinexin) in older mouse and human brain tissue. We characterise vinexin as a negative regulator of autophagy. SORBS3 knockdown increases F-actin structures, which compete with YAP/TAZ for binding to their negative regulators, angiomotins, in the cytosol. This promotes YAP/TAZ translocation into the nucleus, thereby increasing YAP/TAZ transcriptional activity and autophagy. Our data therefore suggest brain autophagy decreases with age in mammals and that this is likely, in part, mediated by increasing levels of vinexin.

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Active Snf1 protein kinase inhibits expression of the Saccharomyces cerevisiae HXT1 glucose transporter gene

Biochemical Journal ◽

10.1042/bj20020984 ◽

2002 ◽

Vol 368 (2) ◽

pp. 657-663 ◽

Cited By ~ 45

Author(s):

Lidia TOMÁS-COBOS ◽

Pascual SANZ

Keyword(s):

Saccharomyces Cerevisiae ◽

Protein Kinase ◽

Glucose Transporter ◽

Negative Regulator ◽

Transporter Gene ◽

Negative Regulators ◽

Gene Encoding ◽

Physiological Conditions ◽

Low Glucose ◽

Glucose Availability

Expression of HXT1, a gene encoding a Saccharomyces cerevisiae low-affinity glucose transporter, is regulated by glucose availability, being activated in the presence of glucose and inhibited when the levels of the sugar are scarce. In this study we show that Snf1 protein kinase participates actively in the inhibition of HXT1 expression. Activation of Snf1, either by physiological conditions (growth in low-glucose conditions) or by eliminating any of its negative regulators, such as Hxk2 or Reg1, leads to an inhibition of HXT1 expression. We also show that Std1, another known negative regulator of HXT1 expression, interacts physically with active Snf1 protein kinase. Std1 also interacts physically with Rgt1, a transcription factor involved in HXT1 expression, suggesting that the transcriptional properties of Rgt1 could be modulated either directly or indirectly by Std1 and Snf1 protein kinase. Finally, we show that Rgt1 interacts physically with Ssn6, a major transcriptional repressor, to regulate negatively HXT1 expression when glucose is depleted.

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Erwinia carotovora Subspecies Produce Duplicate Variants of ExpR, LuxR Homologs That Activate rsmA Transcription but Differ in Their Interactions with N-Acylhomoserine Lactone Signals

Journal of Bacteriology ◽

10.1128/jb.00351-06 ◽

2006 ◽

Vol 188 (13) ◽

pp. 4715-4726 ◽

Cited By ~ 46

Author(s):

Yaya Cui ◽

Asita Chatterjee ◽

Hiroaki Hasegawa ◽

Arun K. Chatterjee

Keyword(s):

Transcriptional Activity ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Erwinia Carotovora ◽

Negative Regulator ◽

Signaling System ◽

Gene Encoding ◽

Acylhomoserine Lactone ◽

Luxr Homolog

ABSTRACT The N-acylhomoserine lactone (AHL) signaling system comprises a producing system that includes acylhomoserine synthase (AhlI, a LuxI homolog) and a receptor, generally a LuxR homolog. AHL controls exoprotein production in Erwinia carotovora and consequently the virulence for plants. In previous studies we showed that ExpR, a LuxR homolog, is an AHL receptor and that it activates transcription of rsmA, the gene encoding an RNA binding protein which is a global negative regulator of exoproteins and secondary metabolites. An unusual finding was that the transcriptional activity of ExpR was neutralized by AHL. We subsequently determined that the genomes of most strains of E. carotovora subspecies tested possess two copies of the expR gene: expR1, which was previously studied, and expR2, which was the focus of this study. Comparative analysis of the two ExpR variants of E. carotovora subsp. carotovora showed that while both variants activated rsmA transcription, there were significant differences in the patterns of their AHL interactions, the rsmA sequences to which they bound, and their relative efficiencies of activation of rsmA transcription. An ExpR2− mutant produced high levels of exoproteins and reduced levels of RsmA in the absence of AHL. This contrasts with the almost complete inhibition of exoprotein production and the high levels of RsmA production in an AhlI− mutant that was ExpR1−. Our results suggest that ExpR2 activity is responsible for regulating exoprotein production primarily by modulating the levels of an RNA binding protein.

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B-Vitamins, Methylenetetrahydrofolate Reductase (MTHFR) and Hypertension

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000069 ◽

2011 ◽

Vol 81 (4) ◽

pp. 240-244 ◽

Cited By ~ 14

Author(s):

Mary Ward ◽

Carol P Wilson ◽

J J Strain ◽

Geraldine Horigan ◽

John M. Scott ◽

...

Keyword(s):

Blood Pressure ◽

Cardiovascular Disease ◽

Risk Factor ◽

Low Dose ◽

Methylenetetrahydrofolate Reductase ◽

Genetic Determinant ◽

Gene Encoding ◽

Homocysteine Concentration ◽

Homozygous Mutant ◽

B Vitamin

Hypertension is a leading risk factor for cardiovascular disease (CVD) and stroke. A common polymorphism in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR), previously identified as the main genetic determinant of elevated homocysteine concentration and also recognized as a risk factor for CVD, appears to be independently associated with hypertension. The B-vitamin riboflavin is required as a cofactor by MTHFR and recent evidence suggests it may have a role in modulating blood pressure, specifically in those with the homozygous mutant MTHFR 677 TT genotype. If studies confirm that this genetic predisposition to hypertension is correctable by low-dose riboflavin, the findings could have important implications for the management of hypertension given that the frequency of this polymorphism ranges from 3 to 32 % worldwide.

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Regulation of Bacillus subtilis aprE Expression by glnA through Inhibition of scoC and σD-Dependent degR Expression

Journal of Bacteriology ◽

10.1128/jb.00049-09 ◽

2009 ◽

Vol 191 (9) ◽

pp. 3050-3058 ◽

Cited By ~ 12

Author(s):

Sadanobu Abe ◽

Ayako Yasumura ◽

Teruo Tanaka

Keyword(s):

Bacillus Subtilis ◽

Glutamine Synthetase ◽

Alkaline Protease ◽

Negative Regulator ◽

Negative Regulators ◽

Global Regulation ◽

Positive Regulation ◽

Expression Levels ◽

Negative Effect ◽

Positive Effect

ABSTRACT Expression of the gene for the extracellular alkaline protease (aprE) of Bacillus subtilis is subject to regulation by many positive and negative regulators. We have found that aprE expression was increased by disruption of the glutamine synthetase gene glnA. The increase in aprE expression was attributed to a decreased in expression of scoC, which encodes a negative regulator of aprE expression. The glnA effect on scoC expression was abolished by further disruption of tnrA, indicating that aprE expression is under global regulation through TnrA. In the scoC background, however, aprE expression was decreased by glnA deletion, and it was shown that the decrease was due to a defect in positive regulation by DegU. Among the genes that affect aprE expression through DegU, the expression of degR, encoding a protein that stabilizes phosphorylated DegU, was inhibited by glnA deletion. It was further shown that the decrease in degR expression by glnA deletion was caused by inhibition of the expression of sigD, encoding the σD factor, which is required for degR expression. In accordance with these findings, the expression levels of aprE-lacZ in glnA scoC degR and scoC degR strains were identical. These results led us to conclude that glnA deletion brings about two effects on aprE expression, i.e., a positive effect through inhibition of scoC expression and a negative effect through inhibition of degR expression, with the former predominating over the latter.

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Controlled Transcription of Regulator Gene carS by Tet-on or by a Strong Promoter Confirms Its Role as a Repressor of Carotenoid Biosynthesis in Fusarium fujikuroi

Microorganisms ◽

10.3390/microorganisms9010071 ◽

2020 ◽

Vol 9 (1) ◽

pp. 71

Author(s):

Julia Marente ◽

Javier Avalos ◽

M. Carmen Limón

Keyword(s):

Wild Strain ◽

Ring Finger ◽

Carotenoid Biosynthesis ◽

Negative Regulator ◽

Fusarium Fujikuroi ◽

Structural Genes ◽

Gene Encoding ◽

In The Wild ◽

Set Up

Carotenoid biosynthesis is a frequent trait in fungi. In the ascomycete Fusarium fujikuroi, the synthesis of the carboxylic xanthophyll neurosporaxanthin (NX) is stimulated by light. However, the mutants of the carS gene, encoding a protein of the RING finger family, accumulate large NX amounts regardless of illumination, indicating the role of CarS as a negative regulator. To confirm CarS function, we used the Tet-on system to control carS expression in this fungus. The system was first set up with a reporter mluc gene, which showed a positive correlation between the inducer doxycycline and luminescence. Once the system was improved, the carS gene was expressed using Tet-on in the wild strain and in a carS mutant. In both cases, increased carS transcription provoked a downregulation of the structural genes of the pathway and albino phenotypes even under light. Similarly, when the carS gene was constitutively overexpressed under the control of a gpdA promoter, total downregulation of the NX pathway was observed. The results confirmed the role of CarS as a repressor of carotenogenesis in F. fujikuroi and revealed that its expression must be regulated in the wild strain to allow appropriate NX biosynthesis in response to illumination.

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Aberrant PTEN expression in response to progesterone reduces endometriotic stromal cell apoptosis

Reproduction ◽

10.1530/rep-16-0322 ◽

2017 ◽

Vol 153 (1) ◽

pp. 11-21 ◽

Cited By ~ 4

Author(s):

JongYeob Choi ◽

MinWha Jo ◽

EunYoung Lee ◽

Seongsoo Hwang ◽

DooSeok Choi

Keyword(s):

Stromal Cells ◽

Human Cancer ◽

Negative Regulator ◽

Pten Expression ◽

Endometrial Cell ◽

Endometrial Stromal Cells ◽

Human Cancer Cells ◽

Subsequent Decrease ◽

Autophagy Induction ◽

Mtor Activity

In some human cancer cells, PTEN (phosphatase and tensin homolog deleted on chromosome 10) is known to regulate autophagy induction positively through the inhibition of PI3K/AKT pathway, leading to the activation of mTOR, a major negative regulator of autophagy. Recent studies reported that PTEN expression is abnormally decreased in endometriotic lesions. In endometriosis, abnormal PTEN expression may contribute to the alteration of endometrial cell autophagy, which may affect apoptosis because endometrial cell autophagy is directly involved in the regulation of apoptosis. To test this hypothesis, we evaluated the involvement of PTEN in the regulation of autophagy induction in human normal endometrial stromal cells (NESCs). In addition, we sought to determine whether aberrant PTEN expression in endometriotic cyst stromal cells (ECSCs) is associated with autophagy dysregulation, and a subsequent decrease in apoptosis. Our results show that PTEN expression was enhanced by progesterone treatment in NESCs. Subsequently, autophagy and apoptosis induction increased through the inhibition of AKT and mTOR activity. This progesterone-induced increase in apoptosis was reversed by the inhibition of autophagy induction using either mifepristone (progesterone receptor modulator) or PTEN inhibitor. In contrast, progesterone had no significant effects on PTEN expression, AKT, mTOR activity, autophagy or apoptosis in ECSCs. Furthermore, in contrast to normal eutopic endometrium, endometriotic tissues have constant PTEN expression, autophagy and apoptosis throughout the menstrual cycle. In conclusion, our results suggest abnormal PTEN expression in response to progesterone was observed in ECSCs, which led to the dysregulation of autophagy induction via AKT/mTOR signalling and a subsequent decrease in apoptosis.

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Lipoprotein(a) as a unique primary risk factor for early atherosclerotic peripheral arterial disease

BMJ Case Reports ◽

10.1136/bcr-2021-243231 ◽

2021 ◽

Vol 14 (6) ◽

pp. e243231

Author(s):

John Mayo ◽

Thomas Hoffman ◽

Ryan Smith ◽

Dwight Kellicut

Keyword(s):

Risk Factor ◽

Cardiovascular Diseases ◽

Peripheral Arterial Disease ◽

Arterial Disease ◽

Common Condition ◽

Elevated Plasma ◽

Early Screening ◽

Lipoprotein A ◽

Peripheral Arterial ◽

Primary Risk Factor

Elevated plasma lipoprotein(a) is a relatively common condition that contributes to many cardiovascular diseases. However, the awareness and testing for this condition remain low. Herein, we present a case of an otherwise healthy and active man who developed symptoms of peripheral arterial disease starting at age 49, and was found to have hyper-lipoprotein(a) as his only notable risk factor. Diagnosis was not made until years later, after an extensive workup. Upon further screening, he was also found to have subclinical coronary and carotid artery atherosclerotic disease. The patient was treated with aspirin, statin, niacin and angioplasty to bilateral superficial femoral arteries with good symptom resolution. Early screening of his son also revealed a similarly elevated lipoprotein(a) level. It is important to raise awareness of this condition and its relationship to early-onset peripheral arterial disease so patients and their families can be appropriately identified, counselled and treated.

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Unusual Starch Degradation Pathway via Cyclodextrins in the Hyperthermophilic Sulfate-Reducing Archaeon Archaeoglobus fulgidus Strain 7324

Journal of Bacteriology ◽

10.1128/jb.01136-07 ◽

2007 ◽

Vol 189 (24) ◽

pp. 8901-8913 ◽

Cited By ~ 19

Author(s):

Antje Labes ◽

Peter Schönheit

Keyword(s):

Degradation Pathway ◽

Archaeoglobus Fulgidus ◽

Starch Degradation ◽

Cyclodextrin Glucanotransferase ◽

Gene Encoding ◽

Thermococcus Litoralis ◽

Sulfate Reducing ◽

Combined Action ◽

Archaeoglobus Fulgidus Strain 7324 ◽

Modified Embden Meyerhof Pathway

ABSTRACT The hyperthermophilic archaeon Archaeoglobus fulgidus strain 7324 has been shown to grow on starch and sulfate and thus represents the first sulfate reducer able to degrade polymeric sugars. The enzymes involved in starch degradation to glucose 6-phosphate were studied. In extracts of starch-grown cells the activities of the classical starch degradation enzymes, α-amylase and amylopullulanase, could not be detected. Instead, evidence is presented here that A. fulgidus utilizes an unusual pathway of starch degradation involving cyclodextrins as intermediates. The pathway comprises the combined action of an extracellular cyclodextrin glucanotransferase (CGTase) converting starch to cyclodextrins and the intracellular conversion of cyclodextrins to glucose 6-phosphate via cyclodextrinase (CDase), maltodextrin phosphorylase (Mal-P), and phosphoglucomutase (PGM). These enzymes, which are all induced after growth on starch, were characterized. CGTase catalyzed the conversion of starch to mainly β-cyclodextrin. The gene encoding CGTase was cloned and sequenced and showed highest similarity to a glucanotransferase from Thermococcus litoralis. After transport of the cyclodextrins into the cell by a transport system to be defined, these molecules are linearized via a CDase, catalyzing exclusively the ring opening of the cyclodextrins to the respective maltooligodextrins. These are degraded by a Mal-P to glucose 1-phosphate. Finally, PGM catalyzes the conversion of glucose 1-phosphate to glucose 6-phosphate, which is further degraded to pyruvate via the modified Embden-Meyerhof pathway.

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Jjj1 Is a Negative Regulator of Pdr1-Mediated Fluconazole Resistance in Candida glabrata

mSphere ◽

10.1128/msphere.00466-17 ◽

2018 ◽

Vol 3 (1) ◽

Cited By ~ 6

Author(s):

Sarah G. Whaley ◽

Kelly E. Caudle ◽

Lucia Simonicova ◽

Qing Zhang ◽

W. Scott Moye-Rowley ◽

...

Keyword(s):

Fungal Pathogen ◽

Candida Glabrata ◽

Antifungal Agents ◽

Common Species ◽

Negative Regulator ◽

Gene Encoding ◽

Fluconazole Resistance ◽

Mechanism Of Resistance ◽

Primary Mechanism ◽

Activating Mutation

Candida glabrata is the second most common species of Candida recovered from patients with invasive candidiasis. The increasing number of infections due to C. glabrata, combined with its high rates of resistance to the commonly used, well-tolerated azole class of antifungal agents, has limited the use of this antifungal class. This has led to the preferential use of echinocandins as empirical treatment for serious Candida infections. The primary mechanism of resistance found in clinical isolates is the presence of an activating mutation in the gene encoding the transcription factor Pdr1 that results in upregulation of one or more of the efflux pumps Cdr1, Pdh1, and Snq2. By developing a better understanding of this mechanism of resistance to the azoles, it will be possible to develop strategies for reclaiming the utility of the azole antifungals against this important fungal pathogen.

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Negative Regulatory Loop between Microphthalmia-Associated Transcription Factor (MITF) and Notch Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms20030576 ◽

2019 ◽

Vol 20 (3) ◽

pp. 576 ◽

Cited By ~ 1

Author(s):

Tamar Golan ◽

Carmit Levy

Keyword(s):

Transcription Factor ◽

Notch Signaling ◽

Transcriptional Activity ◽

Treatment Resistance ◽

Gene Encoding ◽

Reciprocal Interactions ◽

Melanoma Progression ◽

Regulatory Loop ◽

Signaling Activation ◽

Mitf Expression

Melanoma, a melanocyte-origin neoplasm, is a highly metastatic and treatment-resistance cancer. While it is well established that notch signaling activation promotes melanoma progression, little is known about the reciprocal interactions between Notch signaling and melanoma-specific pathways. Here we reveal a negative regulatory loop between Notch signaling and microphthalmia-associated transcription factor (MITF), the central regulator of melanoma progression and the driver of melanoma plasticity. We further demonstrate that Notch signaling activation, in addition to the known competition-based repression mechanism of MITF transcriptional activity, inhibits the transcription of MITF, leading to a decrease in MITF expression. We also found that MITF binds to the promoter of the gene encoding the master regulator of Notch signaling, recombination signal binding protein J kappa (RBPJK), leading to its upregulation. Our findings suggest that, once activated, Notch signaling represses MITF signaling to maintain the melanoma invasiveness and metastatic phenotype.

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