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1.
bioRxiv ; 2023 Aug 06.
Article in English | MEDLINE | ID: mdl-37577631

ABSTRACT

The interactions that cells in Drosophila imaginal discs have with their neighbors are known to regulate their ability to survive. In a screen of genes encoding cell surface proteins for gene knockdowns that affect the size or shape of mutant clones, we found that clones of cells with reduced levels of echinoid (ed) are fewer, smaller, and can be eliminated during development. In contrast, discs composed mostly of ed mutant tissue are overgrown. We find that ed mutant tissue has lower levels of the anti-apoptotic protein Diap1 and has increased levels of apoptosis which is consistent with the observed underrepresentation of ed mutant clones and the slow growth of ed mutant tissue. The eventual overgrowth of ed mutant tissue results not from accelerated growth, but from prolonged growth resulting from a failure to arrest growth at the appropriate final size. Ed has previously been shown to physically interact with multiple Hippo-pathway components and it has been proposed to promote Hippo pathway signaling, to exclude Yorkie (Yki) from the nucleus, and restrain the expression of Yki-target genes. We did not observe changes in Yki localization in ed mutant tissue and found decreased levels of expression of several Yorkie-target genes, findings inconsistent with the proposed effect of Ed on Yki. We did, however, observe increased expression of several Yki-target genes in wild-type cells neighboring ed mutant cells, which may contribute to elimination of ed mutant clones. Thus, ed has two distinct functions: an anti-apoptotic function by maintaining Diap1 levels, and a function to arrest growth at the appropriate final size. Both of these are unlikely to be explained by a simple effect on the Hippo pathway.

2.
bioRxiv ; 2023 Mar 17.
Article in English | MEDLINE | ID: mdl-36993542

ABSTRACT

An epithelium in a living organism seldom develops in isolation. Rather, most epithelia are tethered to other epithelial or non-epithelial tissues, necessitating growth coordination between layers. We investigated how two tethered epithelial layers of the Drosophila larval wing imaginal disc, the disc proper (DP) and the peripodial epithelium (PE), coordinate their growth. DP growth is driven by the morphogens Hedgehog (Hh) and Dpp, but regulation of PE growth is poorly understood. We find that the PE adapts to changes in growth rates of the DP, but not vice versa, suggesting a "leader and follower" mechanism. Moreover, PE growth can occur by cell shape changes, even when proliferation is inhibited. While Hh and Dpp pattern gene expression in both layers, growth of the DP is exquisitely sensitive to Dpp levels, while growth of the PE is not; the PE can achieve an appropriate size even when Dpp signaling is inhibited. Instead, both the growth of the PE and its accompanying cell shape changes require the activity of two components of the mechanosensitive Hippo pathway, the DNA-binding protein Scalloped (Sd) and its co-activator (Yki), which could allow the PE to sense and respond to forces generated by DP growth. Thus, an increased reliance on mechanically-dependent growth mediated by the Hippo pathway, at the expense of morphogen-dependent growth, enables the PE to evade layer-intrinsic growth control mechanisms and coordinate its growth with the DP. This provides a potential paradigm for growth coordination between different components of a developing organ.

3.
Curr Biol ; 32(15): 3350-3364.e6, 2022 08 08.
Article in English | MEDLINE | ID: mdl-35820420

ABSTRACT

An important unanswered question in regenerative biology is to what extent regeneration is accomplished by the reactivation of gene regulatory networks used during development versus the activation of regeneration-specific transcriptional programs. Following damage, Drosophila imaginal discs, the larval precursors of adult structures, can regenerate missing portions by localized proliferation of damage-adjacent tissue. Using single-cell transcriptomics in regenerating wing discs, we have obtained a comprehensive view of the transcriptome of regenerating discs and identified two regeneration-specific cell populations within the blastema, Blastema1 and Blastema2. Collectively, these cells upregulate multiple genes encoding secreted proteins that promote regeneration including Pvf1, upd3, asperous, Mmp1, and the maturation delaying factor Ilp8. Expression of the transcription factor Ets21C is restricted to this regenerative secretory zone; it is not expressed in undamaged discs. Ets21C expression is activated by the JNK/AP-1 pathway, and it can function in a type 1 coherent feedforward loop with AP-1 to sustain expression of downstream genes. Without Ets21C function, the blastema cells fail to maintain the expression of a number of genes, which leads to premature differentiation and severely compromised regeneration. As Ets21C is dispensable for normal development, these observations indicate that Ets21C orchestrates a regeneration-specific gene regulatory network. We have also identified cells resembling both Blastema1 and Blastema2 in scribble tumorous discs. They express the Ets21C-dependent gene regulatory network, and eliminating Ets21C function reduces tumorous growth. Thus, mechanisms that function during regeneration can be co-opted by tumors to promote aberrant growth.


Subject(s)
Drosophila Proteins , Imaginal Discs , Animals , Drosophila/physiology , Drosophila Proteins/metabolism , Drosophila melanogaster/metabolism , Egg Proteins , Proto-Oncogene Proteins c-ets , Transcription Factor AP-1 , Wings, Animal/physiology
4.
Article in English | MEDLINE | ID: mdl-34872971

ABSTRACT

Imaginal discs are simple epithelial sacs found in Drosophila larvae, which generate adult structures including wings and legs. The first studies of imaginal disc regeneration involved technically challenging transplantation experiments. Yet despite the difficulty, many aspects of regeneration including wound healing, blastema formation, and the repatterning of regenerated tissue were characterized. An important discovery was the phenomenon of transdetermination, where a small group of cells in regenerating tissue collectively switch fate ("collective cell reprogramming"). The development of genetic tissue-ablation systems over the last 12 years has energized this field, by making experiments less technically challenging, more reproducible, and by incorporating additional genetic analysis. Recent progress includes defining mechanistic links between early responses to wounding and the signaling pathways that drive proliferation, uncovering a role for localized silencing of damage-responsive enhancers to limit regenerative capacity as tissues mature, and identifying genes that maintain cellular plasticity within acceptable limits during regeneration.


Subject(s)
Drosophila Proteins , Imaginal Discs , Animals , Imaginal Discs/metabolism , Drosophila , Wings, Animal/metabolism , Drosophila Proteins/metabolism , Signal Transduction , Drosophila melanogaster/metabolism
5.
Elife ; 102021 03 22.
Article in English | MEDLINE | ID: mdl-33749594

ABSTRACT

In both vertebrates and invertebrates, generating a functional appendage requires interactions between ectoderm-derived epithelia and mesoderm-derived cells. To investigate such interactions, we used single-cell transcriptomics to generate a temporal cell atlas of the Drosophila wing disc from two developmental time points. Using these data, we visualized gene expression using a multilayered model of the wing disc and cataloged ligand-receptor pairs that could mediate signaling between epithelial cells and adult muscle precursors (AMPs). We found that localized expression of the fibroblast growth factor ligands, Thisbe and Pyramus, in the disc epithelium regulates the number and location of the AMPs. In addition, Hedgehog ligand from the epithelium activates a specific transcriptional program within adjacent AMP cells, defined by AMP-specific targets Neurotactin and midline, that is critical for proper formation of direct flight muscles. More generally, our annotated temporal cell atlas provides an organ-wide view of potential cell-cell interactions between epithelial and myogenic cells.


Subject(s)
Drosophila melanogaster/growth & development , Drosophila melanogaster/genetics , Gene Expression Regulation, Developmental , Imaginal Discs/growth & development , Transcriptome , Animals , Epithelium/physiology , Imaginal Discs/metabolism , Larva/growth & development , Larva/metabolism , Myoblasts/physiology , Single-Cell Analysis , Wings, Animal/growth & development , Wings, Animal/metabolism
6.
EMBO Rep ; 22(4): e51861, 2021 04 07.
Article in English | MEDLINE | ID: mdl-33629503

ABSTRACT

While the membrane potential of cells has been shown to be patterned in some tissues, specific roles for membrane potential in regulating signalling pathways that function during development are still being established. In the Drosophila wing imaginal disc, Hedgehog (Hh) from posterior cells activates a signalling pathway in anterior cells near the boundary which is necessary for boundary maintenance. Here, we show that membrane potential is patterned in the wing disc. Anterior cells near the boundary, where Hh signalling is most active, are more depolarized than posterior cells across the boundary. Elevated expression of the ENaC channel Ripped Pocket (Rpk), observed in these anterior cells, requires Hh. Antagonizing Rpk reduces depolarization and Hh signal transduction. Using genetic and optogenetic manipulations, in both the wing disc and the salivary gland, we show that membrane depolarization promotes membrane localization of Smoothened and augments Hh signalling, independently of Patched. Thus, membrane depolarization and Hh-dependent signalling mutually reinforce each other in cells immediately anterior to the compartment boundary.


Subject(s)
Drosophila Proteins , Hedgehog Proteins , Animals , Drosophila/genetics , Drosophila/metabolism , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Hedgehog Proteins/genetics , Imaginal Discs/metabolism , Membrane Potentials , Signal Transduction , Wings, Animal/metabolism
7.
Sci Adv ; 6(50)2020 12.
Article in English | MEDLINE | ID: mdl-33298454

ABSTRACT

During development, tissue-specific patterns of gene expression are established by transcription factors and then stably maintained via epigenetic mechanisms. Cancer cells often express genes that are inappropriate for that tissue or developmental stage. Here, we show that high activity levels of Yki, the Hippo pathway coactivator that causes overgrowth in Drosophila imaginal discs, can also disrupt cell fates by altering expression of selector genes like engrailed (en) and Ultrabithorax (Ubx). Posterior clones expressing activated Yki can down-regulate en and express an anterior selector gene, cubitus interruptus (ci). The microRNA bantam and the chromatin regulator Taranis both function downstream of Yki in promoting ci expression. The boundary between Yki-expressing posterior clones and surrounding wild-type cells acquires properties reminiscent of the anteroposterior compartment boundary; Hedgehog signaling pathway activation results in production of Dpp. Thus, at least in principle, heterotypic interactions between Yki-expressing cells and their neighbors could activate boundary-specific signaling mechanisms.


Subject(s)
Drosophila Proteins , Animals , Clone Cells , Drosophila/genetics , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Gene Expression Regulation, Developmental , Hedgehog Proteins/genetics , Hedgehog Proteins/metabolism , Hippo Signaling Pathway , Homeodomain Proteins/genetics , Nuclear Proteins/metabolism , Trans-Activators/genetics , Trans-Activators/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Wings, Animal/metabolism
8.
Elife ; 92020 06 03.
Article in English | MEDLINE | ID: mdl-32490812

ABSTRACT

Like tissues of many organisms, Drosophila imaginal discs lose the ability to regenerate as they mature. This loss of regenerative capacity coincides with reduced damage-responsive expression of multiple genes needed for regeneration. We previously showed that two such genes, wg and Wnt6, are regulated by a single damage-responsive enhancer that becomes progressively inactivated via Polycomb-mediated silencing as discs mature (Harris et al., 2016). Here we explore the generality of this mechanism and identify additional damage-responsive, maturity-silenced (DRMS) enhancers, some near genes known to be required for regeneration such as Mmp1, and others near genes that we now show function in regeneration. Using a novel GAL4-independent ablation system we characterize two DRMS-associated genes, apontic (apt), which curtails regeneration and CG9752/asperous (aspr), which promotes it. This mechanism of suppressing regeneration by silencing damage-responsive enhancers at multiple loci can be partially overcome by reducing activity of the chromatin regulator extra sex combs (esc).


Subject(s)
Drosophila melanogaster/genetics , Enhancer Elements, Genetic , Gene Expression Regulation, Developmental , Imaginal Discs/growth & development , Animals , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/growth & development , Drosophila melanogaster/physiology , Gene Silencing , Imaginal Discs/metabolism , Regeneration
9.
Mol Biol Cell ; 30(14): 1641-1644, 2019 07 01.
Article in English | MEDLINE | ID: mdl-31246542

ABSTRACT

Cancer treatments have, in general, targeted the cancer cell itself. This approach has often been unsuccessful in the long term, especially for solid tumors. Even targeted therapies based on sequencing cancer genomes can be thwarted by genetic heterogeneity within tumors. Furthermore, genomic instability in cancer cells accelerates the generation of variants that are resistant to the treatment. Immunotherapies and anti-angiogenic treatments, which target the tumor-interacting and tumor-adjacent cells, have overcome some of these challenges, suggesting that other methods that target wild-type cells could be valuable in arresting tumor progression. Studies in Drosophila have uncovered mechanisms by which cells within an epithelium can react to neighboring cells that have genetic differences, resulting in the elimination of one population at the expense of another. Some of these mechanisms are now known to be conserved in mammals. The possibility of harnessing such mechanisms to empower normal epithelial cells to eliminate their precancerous neighbors before they develop into fully fledged cancers is an area of research that merits more attention.


Subject(s)
Epithelium/pathology , Homeostasis , Neoplasms/pathology , Animals , Drosophila melanogaster/physiology , Humans , Mammals/physiology
10.
Life Sci Alliance ; 1(6): e201800216, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30515478

ABSTRACT

Developmental transitions are often triggered by a neuroendocrine axis and can be contingent upon multiple organs achieving sufficient growth and maturation. How the neurodendocrine axis senses the size and maturity of peripheral organs is not known. In Drosophila larvae, metamorphosis is triggered by a sharp increase in the level of the steroid hormone ecdysone, secreted by the prothoracic gland (PG). Here, we show that the BMP2/4 ortholog Dpp can function as a systemic signal to regulate developmental timing. Dpp from peripheral tissues, mostly imaginal discs, can reach the PG and inhibit ecdysone biosynthesis. As the discs grow, reduced Dpp signaling in the PG is observed, consistent with the possibility that Dpp functions in a checkpoint mechanism that prevents metamorphosis when growth is insufficient. Indeed, upon starvation early in the third larval instar, reducing Dpp signaling in the PG abrogates the critical-weight checkpoint which normally prevents pupariation under these conditions. We suggest that increased local trapping of morphogen within tissues as they grow would reduce circulating levels and hence provide a systemic readout of their growth status.

11.
Elife ; 72018 01 26.
Article in English | MEDLINE | ID: mdl-29372681

ABSTRACT

Regeneration following tissue damage often necessitates a mechanism for cellular re-programming, so that surviving cells can give rise to all cell types originally found in the damaged tissue. This process, if unchecked, can also generate cell types that are inappropriate for a given location. We conducted a screen for genes that negatively regulate the frequency of notum-to-wing transformations following genetic ablation and regeneration of the wing pouch, from which we identified mutations in the transcriptional co-repressor C-terminal Binding Protein (CtBP). When CtBP function is reduced, ablation of the pouch can activate the JNK/AP-1 and JAK/STAT pathways in the notum to destabilize cell fates. Ectopic expression of Wingless and Dilp8 precede the formation of the ectopic pouch, which is subsequently generated by recruitment of both anterior and posterior cells near the compartment boundary. Thus, CtBP stabilizes cell fates following damage by opposing the destabilizing effects of the JNK/AP-1 and JAK/STAT pathways.


Subject(s)
Alcohol Oxidoreductases/metabolism , DNA-Binding Proteins/metabolism , Drosophila Proteins/metabolism , Drosophila/embryology , Imaginal Discs/embryology , MAP Kinase Kinase 4/metabolism , STAT Transcription Factors/metabolism , Transcription Factors/metabolism , Animals , Cell Differentiation , Gene Expression Regulation
12.
Dev Cell ; 42(6): 561-562, 2017 09 25.
Article in English | MEDLINE | ID: mdl-28950097

ABSTRACT

Normal organ growth requires precise signaling from key developmental pathways, as well as careful coordination between these pathways. In this issue of Developmental Cell, Pascual and colleagues (2017) investigate the dire consequences of simultaneous deregulation of both the Ras and Hippo pathways.


Subject(s)
Protein Serine-Threonine Kinases , Signal Transduction , Intracellular Signaling Peptides and Proteins
13.
Curr Opin Cell Biol ; 48: 10-16, 2017 10.
Article in English | MEDLINE | ID: mdl-28376317

ABSTRACT

Drosophila imaginal discs, the larval precursors of adult structures such as the wing and leg, are capable of regenerating after damage. During the course of regeneration, discs can sometimes generate structures that are appropriate for a different type of disc, a phenomenon termed transdetermination. Until recently, these phenomena were studied by physically fragmenting discs and then transplanting them into the abdomens of adult female flies. This field has experienced a renaissance following the development of genetic ablation systems that can damage precisely defined regions of the disc without the need for surgery. Together with more traditional approaches, these newer methods have generated many novel insights into wound healing, the mechanisms that drive regenerative growth, plasticity during regeneration and systemic effects of tissue damage and regeneration.


Subject(s)
Drosophila melanogaster/growth & development , Drosophila melanogaster/physiology , Imaginal Discs/physiology , Animals , Drosophila Proteins , Drosophila melanogaster/cytology , Eye/cytology , Eye/growth & development , Larva/cytology , Larva/physiology , Regeneration , Wings, Animal/cytology , Wings, Animal/growth & development
14.
Development ; 143(15): 2691-5, 2016 08 01.
Article in English | MEDLINE | ID: mdl-27486229

ABSTRACT

Coincident with the blossoming of the sakura was the 14th annual CDB Symposium hosted by the RIKEN Center for Developmental Biology in Kobe, Japan. This year's meeting, 'Size in Development: Growth, Shape and Allometry' focused on the molecular and cellular mechanisms underlying differences in size and shape and how they have evolved. On display was the power of using diverse approaches ranging from the study of organoids to whole organisms.


Subject(s)
Developmental Biology , Animals , Congresses as Topic , Drosophila Proteins , Embryo, Nonmammalian , Humans , Intracellular Signaling Peptides and Proteins , Japan , Molecular Structure , Organoids , Protein Serine-Threonine Kinases , Signal Transduction
15.
Nat Commun ; 7: 12282, 2016 07 25.
Article in English | MEDLINE | ID: mdl-27452696

ABSTRACT

In most multicellular organisms, homeostasis is contingent upon maintaining epithelial integrity. When unanticipated insults breach epithelial barriers, dormant programmes of tissue repair are immediately activated. However, many of the mechanisms that repair damaged epithelia remain poorly characterized. Here we describe a role for Plexin A (PlexA), a protein with particularly well-characterized roles in axonal pathfinding, in the healing of damaged epithelia in Drosophila. Semaphorins, which are PlexA ligands, also regulate tissue repair. We show that Drosophila PlexA has GAP activity for the Rap1 GTPase, which is known to regulate the stability of adherens junctions. Our observations suggest that the inhibition of Rap1 activity by PlexA in damaged Drosophila epithelia allows epithelial remodelling, thus facilitating wound repair. We also demonstrate a role for Plexin A1, a zebrafish orthologue of Drosophila PlexA, in epithelial repair in zebrafish tail fins. Thus, plexins function in epithelial wound healing in diverse taxa.


Subject(s)
Cell Adhesion Molecules/metabolism , Drosophila melanogaster/metabolism , Epithelium/metabolism , Nerve Tissue Proteins/metabolism , Wound Healing , Zebrafish/metabolism , Actins/metabolism , Adherens Junctions/metabolism , Animal Fins/metabolism , Animals , Epithelial Cells/metabolism , RNA Interference , Signal Transduction
16.
Genetics ; 203(1): 109-18, 2016 05.
Article in English | MEDLINE | ID: mdl-26984059

ABSTRACT

RNA interference (RNAi) has emerged as a powerful way of reducing gene function in Drosophila melanogaster tissues. By expressing synthetic short hairpin RNAs (shRNAs) using the Gal4/UAS system, knockdown is efficiently achieved in specific tissues or in clones of marked cells. Here we show that knockdown by shRNAs is so potent and persistent that even transient exposure of cells to shRNAs can reduce gene function in their descendants. When using the FLP-out Gal4 method, in some instances we observed unmarked "shadow RNAi" clones adjacent to Gal4-expressing clones, which may have resulted from brief Gal4 expression following recombination but prior to cell division. Similarly, Gal4 driver lines with dynamic expression patterns can generate shadow RNAi cells after their activity has ceased in those cells. Importantly, these effects can lead to erroneous conclusions regarding the cell autonomy of knockdown phenotypes. We have investigated the basis of this phenomenon and suggested experimental designs for eliminating ambiguities in interpretation. We have also exploited the persistence of shRNA-mediated knockdown to design a sensitive lineage-tracing method, i-TRACE, which is capable of detecting even low levels of past reporter expression. Using i-TRACE, we demonstrate transient infidelities in the expression of some cell-identity markers near compartment boundaries in the wing imaginal disc.


Subject(s)
Drosophila/genetics , Gene Silencing , Genetic Linkage , Mosaicism , RNA Interference , Animals , Animals, Genetically Modified , Biomarkers , Gene Expression , Gene Knockdown Techniques , Phenotype , RNA, Small Interfering/genetics
17.
Elife ; 52016 Feb 03.
Article in English | MEDLINE | ID: mdl-26840050

ABSTRACT

Many organisms lose the capacity to regenerate damaged tissues as they mature. Damaged Drosophila imaginal discs regenerate efficiently early in the third larval instar (L3) but progressively lose this ability. This correlates with reduced damage-responsive expression of multiple genes, including the WNT genes wingless (wg) and Wnt6. We demonstrate that damage-responsive expression of both genes requires a bipartite enhancer whose activity declines during L3. Within this enhancer, a damage-responsive module stays active throughout L3, while an adjacent silencing element nucleates increasing levels of epigenetic silencing restricted to this enhancer. Cas9-mediated deletion of the silencing element alleviates WNT repression, but is, in itself, insufficient to promote regeneration. However, directing Myc expression to the blastema overcomes repression of multiple genes, including wg, and restores cellular responses necessary for regeneration. Localized epigenetic silencing of damage-responsive enhancers can therefore restrict regenerative capacity in maturing organisms without compromising gene functions regulated by developmental signals.


Subject(s)
Drosophila Proteins/biosynthesis , Drosophila/physiology , Epigenesis, Genetic , Gene Silencing , Imaginal Discs/physiology , Regeneration , Wnt Proteins/biosynthesis , Wnt1 Protein/biosynthesis , Animals
18.
Dev Cell ; 34(3): 255-65, 2015 Aug 10.
Article in English | MEDLINE | ID: mdl-26267393

ABSTRACT

Of fundamental interest to biologists is how organs achieve a reproducible size during development. Studies of the developing Drosophila wing have provided many key insights that will help give a conceptual understanding of the process beyond the fly. In the wing, there is evidence for both "top-down" mechanisms, in which signals emanating from small subsets of cells direct global proliferation, and "bottom-up" mechanisms, in which the final size is an emergent property of local cell-cell interactions. Mechanical forces also appear to have an important role along with the Hippo pathway, which may integrate multiple types of inputs to regulate the extent of growth.


Subject(s)
Drosophila melanogaster/growth & development , Imaginal Discs/growth & development , Wings, Animal/growth & development , Animals , Cell Communication/physiology , Cell Proliferation , Drosophila Proteins/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Organ Size , Protein Serine-Threonine Kinases/metabolism , Signal Transduction/physiology
19.
Cold Spring Harb Perspect Biol ; 8(2): a019174, 2015 Jul 27.
Article in English | MEDLINE | ID: mdl-26216720

ABSTRACT

Although we are used to the idea that many organisms stop growing when they reach a predictable size, in many taxa, growth occurs throughout the life of an organism, a phenomenon referred to as indeterminate growth. Our comparative analysis suggests that indeterminate growth may indeed represent the ancestral condition, whereas the permanent arrest of growth may be a more derived state. Consistent with this idea, in diverse taxa, the basal branches show indeterminate growth, whereas more derived branches arrest their growth. Importantly, in some closely related taxa, the termination of growth has evolved in mechanistically distinct ways. Also, even within a single organism, different organs can differ with respect to whether they terminate their growth or not. Finally, the study of tooth development indicates that, even at the level of a single tissue, multiple determinate patterns of growth can evolve from an ancestral one that is indeterminate.


Subject(s)
Biological Evolution , Invertebrates/growth & development , Vertebrates/growth & development , Animals , Tooth/growth & development
20.
Nat Cell Biol ; 17(4): 362-3, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25812520

ABSTRACT

The kinase AMPK, a sensor of cellular energy stress, has been shown to oppose the growth-promoting activity of YAP, the transcriptional co-activator downstream of the Hippo signalling pathway. This finding may help to explain why the antidiabetic drug metformin, for which AMPK is a key effector, is linked to cancer-protective activity.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Energy Metabolism/physiology , Phosphoproteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Hippo Signaling Pathway , Humans , Hypoglycemic Agents/pharmacology , Metformin/pharmacology , Phosphoproteins/antagonists & inhibitors , Phosphorylation , Signal Transduction , Transcription Factors , YAP-Signaling Proteins
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