An evolutionarily-conserved Wnt3/β-catenin/Sp5 feedback loop restricts head organizer activity in Hydra

AbstractThe Hydra polyp regenerates its head by transforming the gastric tissue below the wound into a head organizer made of two antagonistic cross-reacting components. The activator, previously characterized as Wnt3, drives apical differentiation by acting locally and auto-catalytically. The uncharacterized inhibitor, produced under the control of the activator, prevents ectopic head formation. By crossing RNA-seq data obtained in a β-catenin(RNAi) screen performed in planarians and a quantitative analysis of positional and temporal gene expression in Hydra, we identified Sp5 as a transcription factor that fulfills the head inhibitor properties: a Wnt/β-catenin inducible expression, a graded apical-to-basal expression, a sustained up-regulation during head regeneration, a multi-headed phenotype when knocked-down, a repressing activity on Wnt3 expression. In mammalian cells, Hydra and zebrafish Sp5 repress Wnt3 promoter activity while Hydra Sp5 also auto-activates its expression, possibly via β-catenin and/or Tcf/Lef1 interaction. This work identifies Sp5 as a novel potent feedback loop inhibitor of Wnt/β-catenin signaling across eumetazoans.

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Salt-Inducible Kinase 1 Terminates cAMP Signaling by an Evolutionarily Conserved Negative-Feedback Loop in β-Cells

Diabetes ◽

10.2337/db14-1240 ◽

2015 ◽

Vol 64 (9) ◽

pp. 3189-3202 ◽

Cited By ~ 23

Author(s):

Min-Jung Kim ◽

Su-Kyung Park ◽

Ji-Hyun Lee ◽

Chang-Yun Jung ◽

Dong Jun Sung ◽

...

Keyword(s):

Negative Feedback ◽

Feedback Loop ◽

Camp Signaling ◽

Negative Feedback Loop ◽

Β Cells ◽

Evolutionarily Conserved

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miR-582-5p Is a Tumor Suppressor microRNA Targeting the Hippo-YAP/TAZ Signaling Pathway in Non-Small Cell Lung Cancer

Cancers ◽

10.3390/cancers13040756 ◽

2021 ◽

Vol 13 (4) ◽

pp. 756

Author(s):

Bowen Zhu ◽

Mitheera V ◽

Megan Finch-Edmondson ◽

Yaelim Lee ◽

Yue Wan ◽

...

Keyword(s):

Signaling Pathway ◽

Feedback Loop ◽

Therapeutic Potential ◽

Genetic Alterations ◽

Transcriptional Level ◽

Dependent Manner ◽

Biological Processes ◽

Evolutionarily Conserved ◽

Concomitant Reduction

The Hippo-YAP/TAZ signaling pathway is an evolutionarily conserved signaling pathway involved in a broad spectrum of biological processes, including tumorigenesis. Whilst aberrant Hippo-YAP/TAZ signaling is frequently reported in various cancers, the genetic alterations of this pathway are relatively rare, suggesting regulation at the post-transcriptional level. MicroRNAs play key role in tumorigenesis by regulating gene expression post-transcriptionally. Amongst the cancer-relevant microRNAs, miR-582-5p suppresses cell growth and tumorigenesis by inhibiting the expression of oncogenes, including AKT3, MAP3K2 and NOTCH1. Given the oncogenic role of YAP/TAZ in solid tumors, we scrutinized the possible interplay between miR-582-5p and Hippo-YAP/TAZ signaling. Correlation analysis in NSCLC cells revealed a positive relationship between the expression of mature miR-582-5p and the proportion of phosphorylated YAP/TAZ. Intriguingly, YAP/TAZ knockdown reduced the expression of mature miR-582-5p but increased that of primary miR-582. Overexpression of miR-582-5p resulted in increased phosphorylation of YAP/TAZ with a concomitant reduction in cell proliferation and enhanced apoptosis. Mechanistically, we find that miR-582-5p targets actin regulators NCKAP1 and PIP5K1C, which may be responsible for the observed alteration in F-actin, known to modulate YAP/TAZ. We postulate that regulation of the actin cytoskeleton by miR-582-5p may attenuate YAP/TAZ activity. Altogether, this study reveals a novel mechanism of YAP/TAZ regulation by miR-582-5p in a cytoskeleton-dependent manner and suggests a negative feedback loop, highlighting the therapeutic potential of restoring miR-582-5p expression in treating NSCLC.

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A Creb3-Like Transcription Factor Coordinates ER Function upon Food Intake to Regulate Lipid Metabolism

10.1101/2021.03.13.435227 ◽

2021 ◽

Author(s):

Haris A. Khan ◽

Ming Toh ◽

Tamás Schauer ◽

Rory J. Beresford ◽

Paula Ortega-Prieto ◽

...

Keyword(s):

Transcription Factor ◽

Lipid Metabolism ◽

Feeding Behavior ◽

Transcriptional Activation ◽

Feedback Loop ◽

Protein Sorting ◽

Nutrient Storage ◽

Intracellular Organelle ◽

Evolutionarily Conserved ◽

Regulate Lipid Metabolism

SUMMARYIngestion of nutrients elicits essential physiological responses, including absorption, digestion, cessation of feeding and nutrient storage. The endoplasmic reticulum (ER) is central to this nutritional homeostasis, since it regulates intracellular organelle function, drives intercellular communication and promotes metabolite distribution. We identified theDrosophilaCreb3L-family transcription factor, CrebA, as the key metabolic regulator of ER function, thereby affecting lipid metabolism and feeding behavior. In response to feeding, CrebA activity is rapidly and transiently activated. CrebA directly drives the expression of the ER protein sorting machinery. We demonstrate that CrebA levels regulate lipid metabolism through lipoprotein secretion into the hemolymph and suppress feeding behavior. Further, CrebA mouse homologs are also upregulated in the liver following feeding and drive the transcriptional activation of ER protein sorting machinery genes in mammals. Our results reveal an evolutionarily conserved transcription switch which is turned on in response to food ingestion and orchestrates a negative feedback loop that promotes satiety by regulating ER function and protein secretion.

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Diphthamide promotes TOR signaling by increasing the translation of proteins in the TORC1 pathway

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2104577118 ◽

2021 ◽

Vol 118 (37) ◽

pp. e2104577118

Author(s):

Yugang Zhang ◽

Zhewang Lin ◽

Julia Zhu ◽

Miao Wang ◽

Hening Lin

Keyword(s):

Feedback Loop ◽

Elongation Factor ◽

Translation Elongation Factor ◽

Tor Signaling ◽

Translation Elongation ◽

Developmental Defects ◽

Elongation Factor 2 ◽

Genome Wide ◽

Mtorc1 Signaling ◽

Evolutionarily Conserved

Diphthamide, a modification found only on translation elongation factor 2 (EF2), was proposed to suppress −1 frameshifting in translation. Although diphthamide is conserved among all eukaryotes, exactly what proteins are affected by diphthamide deletion is not clear in cells. Through genome-wide profiling for a potential −1 frameshifting site, we identified that the target of rapamycin complex 1 (TORC1)/mammalian TORC1 (mTORC1) signaling pathway is affected by deletion of diphthamide. Diphthamide deficiency in yeast suppresses the translation of TORC1-activating proteins Vam6 and Rtc1. Interestingly, TORC1 signaling also promotes diphthamide biosynthesis, suggesting that diphthamide forms a positive feedback loop to promote translation under nutrient-rich conditions. Our results provide an explanation for why diphthamide is evolutionarily conserved and why diphthamide deletion can cause severe developmental defects.

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Goosecoid is not an essential component of the mouse gastrula organizer but is required for craniofacial and rib development

Development ◽

10.1242/dev.121.9.3005 ◽

1995 ◽

Vol 121 (9) ◽

pp. 3005-3012 ◽

Cited By ~ 50

Author(s):

J.A. Rivera-Perez ◽

M. Mallo ◽

M. Gendron-Maguire ◽

T. Gridley ◽

R.R. Behringer

Keyword(s):

Organizer Region ◽

Embryonic Stem ◽

Homeobox Gene ◽

Primary Body ◽

Evolutionarily Conserved ◽

Vertebrate Embryos ◽

Organizer Activity ◽

Craniofacial Defects ◽

Transplantation Experiments

Goosecoid (gsc) is an evolutionarily conserved homeobox gene expressed in the gastrula organizer region of a variety of vertebrate embryos, including zebrafish, Xenopus, chicken and mouse. To understand the role of gsc during mouse embryogenesis, we generated gsc-null mice by gene targeting in embryonic stem cells. Surprisingly, gsc-null embryos gastrulated and formed the primary body axes; gsc-null mice were born alive but died soon after birth with numerous craniofacial defects. In addition, rib fusions and sternum abnormalities were detected that varied depending upon the genetic background. Transplantation experiments suggest that the ovary does not provide gsc function to rescue gastrulation defects. These results demonstrate that gsc is not essential for organizer activity in the mouse but is required later during embryogenesis for craniofacial and rib cage development.

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Apoptosis and development

Essays in Biochemistry ◽

10.1042/bse0390011 ◽

2003 ◽

Vol 39 ◽

pp. 11-24 ◽

Cited By ~ 6

Author(s):

Justin V McCarthy

Keyword(s):

Drosophila Melanogaster ◽

Mammalian Cells ◽

Cell Number ◽

Model Organisms ◽

Biological Processes ◽

Nematode Caenorhabditis Elegans ◽

Apoptotic Pathway ◽

Genetic Pathways ◽

Evolutionarily Conserved ◽

Multicellular Organisms

Apoptosis is an evolutionarily conserved process used by multicellular organisms to developmentally regulate cell number or to eliminate cells that are potentially detrimental to the organism. The large diversity of regulators of apoptosis in mammalian cells and their numerous interactions complicate the analysis of their individual functions, particularly in development. The remarkable conservation of apoptotic mechanisms across species has allowed the genetic pathways of apoptosis determined in lower species, such as the nematode Caenorhabditis elegans and the fruitfly Drosophila melanogaster, to act as models for understanding the biology of apoptosis in mammalian cells. Though many components of the apoptotic pathway are conserved between species, the use of additional model organisms has revealed several important differences and supports the use of model organisms in deciphering complex biological processes such as apoptosis.

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Novel players fine-tune plant trade-offs

Essays in Biochemistry ◽

10.1042/bse0580083 ◽

2015 ◽

Vol 58 ◽

pp. 83-100 ◽

Cited By ~ 25

Author(s):

Selena Gimenez-Ibanez ◽

Marta Boter ◽

Roberto Solano

Keyword(s):

Ubiquitin Ligase ◽

Feedback Loop ◽

Molecular Level ◽

26S Proteasome ◽

Signalling Molecules ◽

Transcriptional Reprogramming ◽

Trade Offs ◽

Jaz Proteins ◽

Regulatory Feedback Loop ◽

Fine Tune

Jasmonates (JAs) are essential signalling molecules that co-ordinate the plant response to biotic and abiotic challenges, as well as co-ordinating several developmental processes. Huge progress has been made over the last decade in understanding the components and mechanisms that govern JA perception and signalling. The bioactive form of the hormone, (+)-7-iso-jasmonyl-l-isoleucine (JA-Ile), is perceived by the COI1–JAZ co-receptor complex. JASMONATE ZIM DOMAIN (JAZ) proteins also act as direct repressors of transcriptional activators such as MYC2. In the emerging picture of JA-Ile perception and signalling, COI1 operates as an E3 ubiquitin ligase that upon binding of JA-Ile targets JAZ repressors for degradation by the 26S proteasome, thereby derepressing transcription factors such as MYC2, which in turn activate JA-Ile-dependent transcriptional reprogramming. It is noteworthy that MYCs and different spliced variants of the JAZ proteins are involved in a negative regulatory feedback loop, which suggests a model that rapidly turns the transcriptional JA-Ile responses on and off and thereby avoids a detrimental overactivation of the pathway. This chapter highlights the most recent advances in our understanding of JA-Ile signalling, focusing on the latest repertoire of new targets of JAZ proteins to control different sets of JA-Ile-mediated responses, novel mechanisms of negative regulation of JA-Ile signalling, and hormonal cross-talk at the molecular level that ultimately determines plant adaptability and survival.

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