scholarly journals De Novo Shoot Regeneration Controlled by HEN1 and TCP3/4 in Arabidopsis

2020 ◽  
Vol 61 (9) ◽  
pp. 1600-1613
Author(s):  
Woorim Yang ◽  
Myung-Hwan Choi ◽  
Bosl Noh ◽  
Yoo-Sun Noh
Keyword(s):  
Shoot Regeneration ◽  
Posttranscriptional Regulation ◽  
De Novo ◽  
Response Regulator ◽  
Negative Regulator ◽  
Body Parts ◽  
Gene Encoding ◽  
Subsequent Increase ◽  
Underlying Mechanisms

Abstract Plants have the ability to regenerate whole plant body parts, including shoots and roots, in vitro from callus derived from a variety of tissues. However, the underlying mechanisms for this de novo organogenesis, which is based on the totipotency of callus cells, are poorly understood. Here, we report that a microRNA (miRNA)-mediated posttranscriptional regulation plays an important role in de novo shoot regeneration. We found that mutations in HUA ENHANCER 1 (HEN1), a gene encoding a small RNA methyltransferase, cause cytokinin-related defects in de novo shoot regeneration. A hen1 mutation caused a large reduction in the miRNA319 (miR319) level and a subsequent increase in its known target (TCP3 and TCP4) transcript levels. TCP transcription factors redundantly inhibited shoot regeneration and directly activated the expression of a negative regulator of cytokinin response ARABIDOPSIS THALIANA RESPONSE REGULATOR 16 (ARR16). A tcp4 mutation at least partly rescued the shoot-regeneration defect and derepression of ARR16 in hen1. These findings demonstrate that the miR319-TCP3/4-ARR16 axis controls de novo shoot regeneration by modulating cytokinin responses.

scholarly journals Positive and Negative Transcriptional Regulators of Glutathione-Dependent Formaldehyde Metabolism

2004 ◽  
Vol 186 (23) ◽  
pp. 7914-7925 ◽  
Author(s):  
Jason W. Hickman ◽  
Vernon C. Witthuhn ◽  
Miguel Dominguez ◽  
Timothy J. Donohue
Keyword(s):  
Histidine Kinase ◽  
Response Regulator ◽  
Transcription Activation ◽  
Negative Regulator ◽  
Acetyl Phosphate ◽  
Gene Encoding ◽  
Formaldehyde Metabolism ◽  
Dependent Pathway ◽  
Direct Activator

ABSTRACT A glutathione (GSH)-dependent pathway is used for formaldehyde metabolism by a wide variety of prokaryotes and eukaryotes. In this pathway, S-hydroxymethylglutathione, produced by the reaction of formaldehyde with the thiolate moiety of glutathione, is the substrate for a GSH-dependent formaldehyde dehydrogenase (GSH-FDH). While expression of GSH-FDH often increases in the presence of metabolic or exogenous sources of formaldehyde, little is known about the factors that regulate this response. Here, we identify two signal transduction pathways that regulate expression of adhI, the gene encoding GSH-FDH, in Rhodobacter sphaeroides. The loss of the histidine kinase response regulator pair RfdRS or the histidine kinase RfdS increases adhI transcription in the absence of metabolic sources of formaldehyde. Cells lacking RfdRS further increase adhI expression in the presence of metabolic sources of formaldehyde (methanol), suggesting that this negative regulator of GSH-FDH expression does not respond to this compound. In contrast, mutants lacking the histidine kinase response regulator pair AfdRS or the histidine kinase AfdS cannot induce adhI expression in the presence of either formaldehyde or metabolic sources of this compound. AfdR stimulates activity of the adhI promoter in vitro, indicating that this protein is a direct activator of GSH-FDH expression. Activation by AfdR is detectable only after incubation of the protein with acetyl phosphate, suggesting that phosphorylation is necessary for transcription activation. Activation of adhI transcription by acetyl-phosphate-treated AfdR in vitro is inhibited by a truncated RfdR protein, suggesting that this protein is a direct repressor of GSH-FDH expression. Together, the data indicate that AfdRS and RfdRS positively and negatively regulate adhI transcription in response to different signals.

scholarly journals Dual modulation of Ras-Mnk and PI3K-AKT-mTOR pathways: A Novel c-FLIP inhibitory mechanism of 3-AWA mediated translational attenuation through dephosphorylation of eIF4E

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Reyaz ur Rasool ◽  
Bilal Rah ◽  
Hina Amin ◽  
Debasis Nayak ◽  
Souneek Chakraborty ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Cell Cycle Progression ◽  
De Novo ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Apoptosis Resistance ◽  
Nih3t3 Cells ◽  
Eukaryotic Translation ◽  
Underlying Mechanisms

Abstract The eukaryotic translation initiation factor 4E (eIF4E) is considered as a key survival protein involved in cell cycle progression, transformation and apoptosis resistance. Herein, we demonstrate that medicinal plant derivative 3-AWA (from Withaferin A) suppressed the proliferation and metastasis of CaP cells through abrogation of eIF4E activation and expression via c-FLIP dependent mechanism. This translational attenuation prevents the de novo synthesis of major players of metastatic cascades viz. c-FLIP, c-Myc and cyclin D1. Moreover, the suppression of c-FLIP due to inhibition of translation initiation complex by 3-AWA enhanced FAS trafficking, BID and caspase 8 cleavage. Further ectopically restored c-Myc and GFP-HRas mediated activation of eIF4E was reduced by 3-AWA in transformed NIH3T3 cells. Detailed underlying mechanisms revealed that 3-AWA inhibited Ras-Mnk and PI3-AKT-mTOR, two major pathways through which eIF4E converges upon eIF4F hub. In addition to in vitro studies, we confirmed that 3-AWA efficiently suppressed tumor growth and metastasis in different mouse models. Given that 3-AWA inhibits c-FLIP through abrogation of translation initiation by co-targeting mTOR and Mnk-eIF4E, it (3-AWA) can be exploited as a lead pharmacophore for promising anti-cancer therapeutic development.

Targeting MDM2-dependent serine metabolism as a therapeutic strategy for liposarcoma

2020 ◽  
Vol 12 (547) ◽  
pp. eaay2163
Author(s):  
Madi Y. Cissé ◽  
Samuel Pyrdziak ◽  
Nelly Firmin ◽  
Laurie Gayte ◽  
Maud Heuillet ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Negative Regulator ◽  
Nucleotide Synthesis ◽  
Metabolic Functions ◽  
Xenograft Models ◽  
Well Differentiated ◽  
Serine Metabolism

Well-differentiated and dedifferentiated liposarcomas (LPSs) are characterized by a systematic amplification of the MDM2 oncogene, which encodes a key negative regulator of the p53 pathway. The molecular mechanisms underlying MDM2 overexpression while sparing wild-type p53 in LPS remain poorly understood. Here, we show that the p53-independent metabolic functions of chromatin-bound MDM2 are exacerbated in LPS and mediate an addiction to serine metabolism that sustains nucleotide synthesis and tumor growth. Treatment of LPS cells with Nutlin-3A, a pharmacological inhibitor of the MDM2-p53 interaction, stabilized p53 but unexpectedly enhanced MDM2-mediated control of serine metabolism by increasing its recruitment to chromatin, likely explaining the poor clinical efficacy of this class of MDM2 inhibitors. In contrast, genetic or pharmacological inhibition of chromatin-bound MDM2 by SP141, a distinct MDM2 inhibitor triggering its degradation, or interfering with de novo serine synthesis, impaired LPS growth both in vitro and in clinically relevant patient-derived xenograft models. Our data indicate that targeting MDM2 functions in serine metabolism represents a potential therapeutic strategy for LPS.

scholarly journals A Novel Long Non-Coding RNA-01488 Suppressed Metastasis and Tumorigenesis by Inducing miRNAs That Reduce Vimentin Expression and Ubiquitination of Cyclin E

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1504
Author(s):  
Syuan-Ling Lin ◽  
Yang-Hsiang Lin ◽  
Hsiang-Cheng Chi ◽  
Tzu-Kang Lin ◽  
Wei-Jan Chen ◽  
...  
Keyword(s):  
Human Cancer ◽  
Cyclin E ◽  
Survival Rates ◽  
Negative Regulator ◽  
Vimentin Expression ◽  
Protein Coding ◽  
Tumorigenic Activity ◽  
Underlying Mechanisms

Long intergenic non-coding RNAs (lincRNAs) play important roles in human cancer development, including cell differentiation, apoptosis, and tumor progression. However, their underlying mechanisms of action are largely unknown at present. In this study, we focused on a novel suppressor lincRNA that has the potential to inhibit progression of human hepatocellular carcinoma (HCC). Our experiments disclosed long intergenic non-protein coding RNA 1488 (LINC01488) as a key negative regulator of HCC. Clinically, patients with high LINC01488 expression displayed greater survival rates and better prognosis. In vitro and in vivo functional assays showed that LINC01488 overexpression leads to significant suppression of cell proliferation and metastasis in HCC. Furthermore, LINC01488 bound to cyclin E to induce its ubiquitination and reduced expression of vimentin mediated by both miR-124-3p/miR-138-5p. Our results collectively indicate that LINC01488 acts as a tumor suppressor that inhibits metastasis and tumorigenesis in HCC via the miR-124-3p/miR-138-5p/vimentin axis. Furthermore, LINC01488 interacts with and degrades cyclin E, which contributes to its anti-tumorigenic activity. In view of these findings, we propose that enhancement of LINC01488 expression could be effective as a potential therapeutic strategy for HCC.

scholarly journals Integrating the Roles for Cytokinin and Auxin in De Novo Shoot Organogenesis: From Hormone Uptake to Signaling Outputs

2021 ◽  
Vol 22 (16) ◽  
pp. 8554
Author(s):  
Martin Raspor ◽  
Václav Motyka ◽  
Abdul Rasheed Kaleri ◽  
Slavica Ninković ◽  
Ljiljana Tubić ◽  
...  
Keyword(s):  
Shoot Regeneration ◽  
De Novo ◽  
Shoot Organogenesis ◽  
In Vitro Regeneration ◽  
Genetic Regulation ◽  
Auxin Signaling ◽  
Plant Tissues ◽  
Cultivated Plant ◽  
The Media

De novo shoot organogenesis (DNSO) is a procedure commonly used for the in vitro regeneration of shoots from a variety of plant tissues. Shoot regeneration occurs on nutrient media supplemented with the plant hormones cytokinin (CK) and auxin, which play essential roles in this process, and genes involved in their signaling cascades act as master regulators of the different phases of shoot regeneration. In the last 20 years, the genetic regulation of DNSO has been characterized in detail. However, as of today, the CK and auxin signaling events associated with shoot regeneration are often interpreted as a consequence of these hormones simply being present in the regeneration media, whereas the roles for their prior uptake and transport into the cultivated plant tissues are generally overlooked. Additionally, sucrose, commonly added to the regeneration media as a carbon source, plays a signaling role and has been recently shown to interact with CK and auxin and to affect the efficiency of shoot regeneration. In this review, we provide an integrative interpretation of the roles for CK and auxin in the process of DNSO, adding emphasis on their uptake from the regeneration media and their interaction with sucrose present in the media to their complex signaling outputs that mediate shoot regeneration.

scholarly journals Phosphorylated AbsA2 Negatively Regulates Antibiotic Production in Streptomyces coelicolor through Interactions with Pathway-Specific Regulatory Gene Promoters

2007 ◽  
Vol 189 (14) ◽  
pp. 5284-5292 ◽  
Author(s):  
Nancy L. McKenzie ◽  
Justin R. Nodwell
Keyword(s):  
Response Regulator ◽  
Antibiotic Production ◽  
Streptomyces Coelicolor ◽  
Regulatory Gene ◽  
Gene Clusters ◽  
Negative Regulator ◽  
Gene Promoters ◽  
Promoter Regions ◽  
Calcium Dependent

ABSTRACT The AbsA two-component signal transduction system, comprised of the sensor kinase AbsA1 and the response regulator AbsA2, acts as a negative regulator of antibiotic production in Streptomyces coelicolor, for which the phosphorylated form of AbsA2 (AbsA2∼P) is the agent of repression. In this study, we used chromatin immunoprecipitation to show that AbsA2 binds the promoter regions of actII-ORF4, cdaR, and redZ, which encode pathway-specific activators for actinorhodin, calcium-dependent antibiotic, and undecylprodigiosin, respectively. We confirm that these interactions also occur in vitro and that the binding of AbsA2 to each gene is enhanced by phosphorylation. Induced expression of actII-ORF4 and redZ in the hyperrepressive absA1 mutant (C542) brought about pathway-specific restoration of actinorhodin and undecylprodigiosin production, respectively. Our results suggest that AbsA2∼P interacts with as many as four sites in the region that includes the actII-ORF4 promoter. These data suggest that AbsA2∼P inhibits antibiotic production by directly interfering with the expression of pathway-specific regulators of antibiotic biosynthetic gene clusters.

scholarly journals Downregulated Recycling Process but Not De Novo Synthesis of Glutathione Limits Antioxidant Capacity of Erythrocytes in Hypoxia

2020 ◽  
Vol 2020 ◽  
pp. 1-17
Author(s):  
Yueming Wang ◽  
Nannan Zhao ◽  
Yanlei Xiong ◽  
Jiashen Zhang ◽  
Dongmei Zhao ◽  
...  
Keyword(s):  
Antioxidant Capacity ◽  
De Novo ◽  
De Novo Synthesis ◽  
Recycling Process ◽  
Stress Injury ◽  
Free Radical Damage ◽  
Oxygen Gradients ◽  
Vitro Model ◽  
Underlying Mechanisms

Red blood cells (RBCs) are susceptible to sustained free radical damage during circulation, while the changes of antioxidant capacity and regulatory mechanism of RBCs under different oxygen gradients remain unclear. Here, we investigated the changes of oxidative damage and antioxidant capacity of RBCs in different oxygen gradients and identified the underlying mechanisms using an in vitro model of the hypoxanthine/xanthine oxidase (HX/XO) system. In the present study, we reported that the hypoxic RBCs showed much higher oxidative stress injury and lower antioxidant capacity compared with normoxic RBCs. In addition, we found that the disturbance of the recycling process, but not de novo synthesis of glutathione (GSH), accounted for the significantly decreased antioxidant capacity of hypoxic RBCs compared to normoxic RBCs. We further elucidated the underlying molecular mechanism by which oxidative phosphorylation of Band 3 blocked the hexose monophosphate pathway (HMP) and decreased NADPH production aggravating the dysfunction of GSH synthesis in hypoxic RBCs under oxidative conditions.

scholarly journals Escherichia coliO157:H7 Lacking theqseBC-Encoded Quorum-Sensing System Outcompetes the Parental Strain in Colonization of Cattle Intestines

2014 ◽  
Vol 80 (6) ◽  
pp. 1882-1892 ◽  
Author(s):  
V. K. Sharma ◽  
T. A. Casey
Keyword(s):  
Quorum Sensing ◽  
Parental Strain ◽  
Response Regulator ◽  
Stress Hormones ◽  
Gene Encoding ◽  
Fecal Shedding ◽  
Sensing System ◽  
Quorum Sensing System ◽  
Parental Level

ABSTRACTTheqseBC-encoded quorum-sensing system regulates the motility ofEscherichia coliO157:H7 in response to bacterial autoinducer 3 (AI-3) and the mammalian stress hormones epinephrine (E) and norepinephrine (NE). TheqseCgene encodes a sensory kinase that autophosphorylates in response to AI-3, E, or NE and subsequently phosphorylates its cognate response regulator QseB. In the absence of QseC, QseB downregulates bacterial motility and virulence in animal models. In this study, we found that 8- to 10-month-old calves orally inoculated with a mixture ofE. coliO157:H7 and its isogenicqseBCmutant showed significantly higher fecal shedding of theqseBCmutant.In vitroanalysis revealed similar growth profiles and motilities of theqseBCmutant and the parental strain in the presence or absence of NE. The magnitudes of the response to NE and expression of flagellar genesflhDandfliCwere also similar for theqseBCmutant and the parental strain. The expression ofler(a positive regulator of the locus of enterocyte effacement [LEE]), theler-regulatedespAgene, and thecsgAgene (encoding curli fimbriae) was increased in theqseBCmutant compared to the parental strain. On the other hand, growth, motility, and transcription offlhD,fliC,ler,espA, andcsgAwere significantly reduced in theqseBCmutant complemented with a plasmid-cloned copy of theqseBCgenes. Thus,in vitromotility and gene expression data indicate that the near-parental level of motility, ability to respond to NE, and enhanced expression of LEE and curli genes might in part be responsible for increased colonization and fecal shedding of theqseBCmutant in calves.

scholarly journals De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Robin N. Stringer ◽  
Bohumila Jurkovicova-Tarabova ◽  
Ivana A. Souza ◽  
Judy Ibrahim ◽  
Tomas Vacik ◽  
...  
Keyword(s):  
Ion Channel ◽  
De Novo ◽  
Epileptic Encephalopathy ◽  
Gene Encoding ◽  
Epileptic Encephalopathies ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Whole Exome ◽  
Heterozygous Variant

AbstractDevelopmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873–4881 duplication) in the SCN8A gene and an inherited heterozygous variant (c.952G > A) in the CACNA1H gene encoding for Nav1.6 voltage-gated sodium and Cav3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Nav1.6 and Cav3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of SCN8A and CACNA1H, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.

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