scholarly journals The transcriptional co-repressor CtBP is a negative regulator of growth that antagonizes the Yorkie and JNK/AP-1 pathways

2019 ◽  
Author(s):  
Taryn M. Sumabat ◽  
Melanie I. Worley ◽  
Brett J. Pellock ◽  
Justin A. Bosch ◽  
Iswar K. Hariharan
Keyword(s):  
Mammalian Cells ◽  
Growth Regulation ◽  
Hippo Pathway ◽  
Growth Control ◽  
Tissue Growth ◽  
Negative Regulator ◽  
Control Mechanisms ◽  
Loss Of Function ◽  
Jnk Pathway ◽  
Multicellular Organisms

AbstractMulticellular organisms require strict growth control mechanisms to ensure that an organ reaches, but does not grossly exceed, its appropriate size and shape. In an unbiased mosaic screen for genes involved in growth regulation, we identified a loss-of-function allele of the gene CtBP that conferred a growth advantage to homozygous mutant tissue. CtBP encodes a transcriptional co-repressor found in diverse organisms, yet its role in regulating tissue growth is not known. We found that CtBP functions as a negative regulator of growth by restricting the expression of the growth-promoting microRNA bantam (ban). ban is a known target of the Hippo pathway effector Yorkie (Yki). We show that loss of CtBP function leads to the activation of a minimal enhancer of ban via both Yki-dependent and AP-1 transcription factor-dependent mechanisms. AP-1 is downstream of the Jun N-terminal Kinase (JNK) pathway and thus JNK could regulate growth during development via ban. Furthermore, we show that distinct isoforms of the AP-1 component Fos differ in their ability to activate this enhancer. Since the orthologous pathways in mammalian cells (YAP/TEAD and AP-1) converge on enhancers implicated in tumor progression, a role for mammalian CtBP proteins at those enhancers merits attention.

scholarly journals The palmitoyltransferase Approximated promotes growth via the Hippo pathway by palmitoylation of Fat

2016 ◽  
Vol 216 (1) ◽  
pp. 265-277 ◽  
Author(s):  
Hitoshi Matakatsu ◽  
Seth S. Blair ◽  
Richard G. Fehon
Keyword(s):  
Posttranslational Modification ◽  
Hippo Pathway ◽  
Growth Control ◽  
Tissue Growth ◽  
Negative Regulator ◽  
Pathway Activity ◽  
Protein Association ◽  
Junctional Region ◽  
Growth Loss ◽  
The Hippo Pathway

The large protocadherin Fat functions to promote Hippo pathway activity in restricting tissue growth. Loss of Fat leads to accumulation of the atypical myosin Dachs at the apical junctional region, which in turn promotes growth by inhibiting Warts. We previously identified Approximated (App), a DHHC domain palmitoyltransferase, as a negative regulator of Fat signaling in growth control. We show here that App promotes growth by palmitoylating the intracellular domain of Fat, and that palmitoylation negatively regulates Fat function. Independently, App also recruits Dachs to the apical junctional region through protein–protein association, thereby stimulating Dachs’s activity in promoting growth. Further, we show that palmitoylation by App functions antagonistically to phosphorylation by Discs-overgrown, which activates Fat. Together, these findings suggest a model in which App promotes Dachs activity by simultaneously repressing Fat via posttranslational modification and recruiting Dachs to the apical junctional region, thereby promoting tissue growth.

scholarly journals Loss offlflTriggers JNK-Dependent Cell Death inDrosophila

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Jiuhong Huang ◽  
Lei Xue
Keyword(s):  
Cell Death ◽  
Function Analysis ◽  
Ectopic Expression ◽  
Negative Regulator ◽  
Loss Of Function ◽  
Jnk Pathway ◽  
Dependent Cell ◽  
Jnk Activation ◽  
First Time

falafel(flfl) encodes aDrosophilahomolog of human SMEK whosein vivofunctions remain elusive. In this study, we performed gain-of-function and loss-of-function analysis inDrosophilaand identified flfl as a negative regulator of JNK pathway-mediated cell death. While ectopic expression offlflsuppresses TNF-triggered JNK-dependent cell death, loss offlflpromotes JNK activation and cell death in the developing eye and wing. These data report for the first time an essential physiological function offlflin maintaining tissue homeostasis and organ development. As the JNK signaling pathway has been evolutionary conserved from fly to human, a similar role of PP4R3 in JNK-mediated physiological process is speculated.

scholarly journals Getting to S: CDK functions and targets on the path to cell-cycle commitment

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2374 ◽  
Author(s):  
Robert P. Fisher
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Growth Conditions ◽  
Control Mechanisms ◽  
Cell Fates ◽  
Cycle Arrest ◽  
Distinct Cell ◽  
Cast Doubt ◽  
Multicellular Organisms

How and when eukaryotic cells make the irrevocable commitment to divide remain central questions in the cell-cycle field. Parallel studies in yeast and mammalian cells seemed to suggest analogous control mechanisms operating during the G1 phase—at Start or the restriction (R) point, respectively—to integrate nutritional and developmental signals and decide between distinct cell fates: cell-cycle arrest or exit versus irreversible commitment to a round of division. Recent work has revealed molecular mechanisms underlying this decision-making process in both yeast and mammalian cells but also cast doubt on the nature and timing of cell-cycle commitment in multicellular organisms. These studies suggest an expanded temporal window of mitogen sensing under certain growth conditions, illuminate unexpected obstacles and exit ramps on the path to full cell-cycle commitment, and raise new questions regarding the functions of cyclin-dependent kinases (CDKs) that drive G1 progression and S-phase entry.

scholarly journals Genome-Wide Screen for Context-Dependent Tumor Suppressors Identified Using in Vivo Models for Neoplasia in Drosophila

2020 ◽  
Vol 10 (9) ◽  
pp. 2999-3008 ◽  
Author(s):  
Casper Groth ◽  
Pooja Vaid ◽  
Aditi Khatpe ◽  
Nelchi Prashali ◽  
Avantika Ahiya ◽  
...  
Keyword(s):  
Large Scale ◽  
Hippo Pathway ◽  
Growth Control ◽  
Growth Factor Receptor ◽  
Tissue Growth ◽  
In Vivo Models ◽  
Genome Wide ◽  
Positive Regulators ◽  
The Hippo Pathway

Abstract Genetic approaches in Drosophila have successfully identified many genes involved in regulation of growth control as well as genetic interactions relevant to the initiation and progression of cancer in vivo. Here, we report on large-scale RNAi-based screens to identify potential tumor suppressor genes that interact with known cancer-drivers: the Epidermal Growth Factor Receptor and the Hippo pathway transcriptional cofactor Yorkie. These screens were designed to identify genes whose depletion drove tissue expressing EGFR or Yki from a state of benign overgrowth into neoplastic transformation in vivo. We also report on an independent screen aimed to identify genes whose depletion suppressed formation of neoplastic tumors in an existing EGFR-dependent neoplasia model. Many of the positives identified here are known to be functional in growth control pathways. We also find a number of novel connections to Yki and EGFR driven tissue growth, mostly unique to one of the two. Thus, resources provided here would be useful to all researchers who study negative regulators of growth during development and cancer in the context of activated EGFR and/or Yki and positive regulators of growth in the context of activated EGFR. Resources reported here are available freely for anyone to use.

scholarly journals Salvador–Warts–Hippo pathway regulates sensory organ development via caspase-dependent nonapoptotic signaling

2019 ◽  
Vol 10 (9) ◽  
Author(s):  
Lan-Hsin Wang ◽  
Nicholas E. Baker
Keyword(s):  
Wnt Signaling ◽  
Cell Fate ◽  
Growth Regulation ◽  
Hippo Pathway ◽  
Size Control ◽  
Negative Regulator ◽  
Sensory Organ ◽  
Neural Precursor ◽  
Cell Fate Determination ◽  
Fate Determination

Abstract The fundamental roles for the Salvador–Warts–Hippo (SWH) pathway are widely characterized in growth regulation and organ size control. However, the function of SWH pathway is less known in cell fate determination. Here we uncover a novel role of the SWH signaling pathway in determination of cell fate during neural precursor (sensory organ precursor, SOP) development. Inactivation of the SWH pathway in SOP of the wing imaginal discs affects caspase-dependent bristle patterning in an apoptosis-independent process. Such nonapoptotic functions of caspases have been implicated in inflammation, proliferation, cellular remodeling, and cell fate determination. Our data indicate an effect on the Wingless (Wg)/Wnt pathway. Previously, caspases were proposed to cleave and activate a negative regulator of Wg/Wnt signaling, Shaggy (Sgg)/GSK3β. Surprisingly, we found that a noncleavable form of Sgg encoded from the endogenous locus after CRISPR-Cas9 modification supported almost normal bristle patterning, indicating that Sgg might not be the main target of the caspase-dependent nonapoptotic process. Collectively, our results outline a new function of SWH signaling that crosstalks to caspase-dependent nonapoptotic signaling and Wg/Wnt signaling in neural precursor development, which might be implicated in neuronal pathogenesis.

scholarly journals The miRNA bantam regulates growth and tumorigenesis by repressing the cell cycle regulator tribbles

2019 ◽  
Vol 2 (4) ◽  
pp. e201900381 ◽  
Author(s):  
Stephan U Gerlach ◽  
Moritz Sander ◽  
Shilin Song ◽  
Héctor Herranz
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Target Genes ◽  
Hippo Pathway ◽  
Growth Control ◽  
Tissue Growth ◽  
Tumor Formation ◽  
Hippo Signaling ◽  
Cell Cycle Regulators ◽  
The Hippo Pathway

One of the fundamental issues in biology is understanding how organ size is controlled. Tissue growth has to be carefully regulated to generate well-functioning organs, and defects in growth control can result in tumor formation. The Hippo signaling pathway is a universal growth regulator and has been implicated in cancer. In Drosophila, the Hippo pathway acts through the miRNA bantam to regulate cell proliferation and apoptosis. Even though the bantam targets regulating apoptosis have been determined, the target genes controlling proliferation have not been identified thus far. In this study, we identify the gene tribbles as a direct bantam target gene. Tribbles limits cell proliferation by suppressing G2/M transition. We show that tribbles regulation by bantam is central in controlling tissue growth and tumorigenesis. We expand our study to other cell cycle regulators and show that deregulated G2/M transition can collaborate with oncogene activation driving tumor formation.

scholarly journals Amotl2a interacts with the Hippo effector Yap1 and the Wnt/β-catenin effector Lef1 to control tissue size in zebrafish

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Sobhika Agarwala ◽  
Sandra Duquesne ◽  
Kun Liu ◽  
Anton Boehm ◽  
Lin Grimm ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Growth Control ◽  
Tissue Growth ◽  
Cell Junction ◽  
Hippo Signaling ◽  
Sensory Organs ◽  
Hippo Signaling Pathway ◽  
Tissue Size ◽  
The Hippo Pathway ◽  
First Time

During development, proliferation must be tightly controlled for organs to reach their appropriate size. While the Hippo signaling pathway plays a major role in organ growth control, how it senses and responds to increased cell density is still unclear. In this study, we use the zebrafish lateral line primordium (LLP), a group of migrating epithelial cells that form sensory organs, to understand how tissue growth is controlled during organ formation. Loss of the cell junction-associated Motin protein Amotl2a leads to overproliferation and bigger LLP, affecting the final pattern of sensory organs. Amotl2a function in the LLP is mediated together by the Hippo pathway effector Yap1 and the Wnt/β-catenin effector Lef1. Our results implicate for the first time the Hippo pathway in size regulation in the LL system. We further provide evidence that the Hippo/Motin interaction is essential to limit tissue size during development.

scholarly journals Impaired Hippo signaling promotes Rho1–JNK-dependent growth

2015 ◽  
Vol 112 (4) ◽  
pp. 1065-1070 ◽  
Author(s):  
Xianjue Ma ◽  
Yujun Chen ◽  
Wenyan Xu ◽  
Nana Wu ◽  
Maoquan Li ◽  
...  
Keyword(s):  
Rho Gtpases ◽  
Hippo Pathway ◽  
Tissue Growth ◽  
Hippo Signaling ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Dependent Growth ◽  
Jnk Activation ◽  
The Hippo Pathway

The Hippo and c-Jun N-terminal kinase (JNK) pathway both regulate growth and contribute to tumorigenesis when dysregulated. Whereas the Hippo pathway acts via the transcription coactivator Yki/YAP to regulate target gene expression, JNK signaling, triggered by various modulators including Rho GTPases, activates the transcription factors Jun and Fos. Here, we show that impaired Hippo signaling induces JNK activation through Rho1. Blocking Rho1–JNK signaling suppresses Yki-induced overgrowth in the wing disk, whereas ectopic Rho1 expression promotes tissue growth when apoptosis is prohibited. Furthermore, Yki directly regulates Rho1 transcription via the transcription factor Sd. Thus, our results have identified a novel molecular link between the Hippo and JNK pathways and implicated the essential role of the JNK pathway in Hippo signaling-related tumorigenesis.

scholarly journals A Genetic Screen in Drosophila To Identify Novel Regulation of Cell Growth by Phosphoinositide Signaling

2019 ◽  
Vol 10 (1) ◽  
pp. 57-67 ◽  
Author(s):  
Vishnu Janardan ◽  
Sanjeev Sharma ◽  
Urbashi Basu ◽  
Padinjat Raghu
Keyword(s):  
Cell Growth ◽  
Growth Regulation ◽  
Growth Control ◽  
Tissue Growth ◽  
Genetic Screen ◽  
Cell Interactions ◽  
Cellular Processes ◽  
Link Type ◽  
Lipid Kinases ◽  
Cell Cell

Phosphoinositides are lipid signaling molecules that regulate several conserved sub-cellular processes in eukaryotes, including cell growth. Phosphoinositides are generated by the enzymatic activity of highly specific lipid kinases and phosphatases. For example, the lipid PIP3, the Class I PI3 kinase that generates it and the phosphatase PTEN that metabolizes it are all established regulators of growth control in metazoans. To identify additional functions for phosphoinositides in growth control, we performed a genetic screen to identify proteins which when depleted result in altered tissue growth. By using RNA-interference mediated depletion coupled with mosaic analysis in developing eyes, we identified and classified additional candidates in the developing Drosophila melanogaster eye that regulate growth either cell autonomously or via cell-cell interactions. We report three genes: Pi3K68D, Vps34 and fwd that are important for growth regulation and suggest that these are likely to act via cell-cell interactions in the developing eye. Our findings define new avenues for the understanding of growth regulation in metazoan tissue development by phosphoinositide metabolizing proteins.

scholarly journals Role of α-Catenin and its mechanosensing properties in the regulation of Hippo/YAP-dependent tissue growth

2019 ◽  
Author(s):  
Ritu Sarpal ◽  
Victoria Yan ◽  
Lidia Kazakova ◽  
Luka Sheppard ◽  
Ulrich Tepass
Keyword(s):  
Growth Regulation ◽  
Tissue Growth ◽  
Binding Domain ◽  
Negative Regulator ◽  
Actin Binding ◽  
Hippo Signaling ◽  
Actin Binding Domain ◽  
Opposing Effects ◽  
Tissue Tension

Abstractα-catenin is a key protein of adherens junctions (AJs) with mechanosensory properties. It also acts as a tumor suppressor that limits tissue growth. Here we analyzed the function of Drosophila α-Catenin (α-Cat) in growth regulation of the wing epithelium. We found that different α-Cat levels led to a differential activation of Hippo/Yorkie or JNK signaling causing tissue overgrowth or degeneration, respectively. α-Cat can modulate Yorkie-dependent tissue growth through recruitment of Ajuba, a negative regulator of Hippo signaling, to AJs but also through a mechanism that does not involve junctional recruitment of Ajuba. Further, both mechanosensory regions of α-Cat, the M region and the actin-binding domain (ABD), contribute to growth regulation. Whereas M is dispensable for α-Cat function in the wing, individual M domains (M1, M2, M3) have opposing effects on growth regulation. In particular, M1 limits Ajuba recruitment. Loss of M1 cause Ajuba hyper-recruitment to AJs promoting tissue-tension independent overgrowth. Although M1 binds Vinculin, Vinculin it is not responsible for this effect. Moreover, disruption of mechanosensing of the α-Cat actin-binding domain affects tissue growth, with enhanced actin interactions stabilizing junctions and leading to tissue overgrowth. Together, our findings indicate that α-Cat acts through multiple mechanisms to control tissue growth, including regulation of AJ stability, mechanosensitive Ajuba recruitment, and dynamic direct F-actin interactions.

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