Bab2 activates JNK signaling to reprogram Drosophila wing disc development

AbstractIn response to cellular stress and damage, certain tissues are able to regenerate and to restore tissue homeostasis. In Drosophila imaginal wing discs, dying cells express mitogens that induce compensatory proliferation in the surrounding tissue. Here we report that high levels of the BTB/POZ transcription factor Bab2 in the posterior compartment of wing discs activates c-Jun N-terminal kinase (JNK) signaling and local, cell-autonomous apoptotic cell death. This in turn triggered the upregulation of the Dpp mitogen and cellular proliferation in the anterior compartment in a JNK-dependent manner. In the posterior compartment, however, dpp expression was suppressed, most likely by direct transcriptional repression by Bab2. This dual-mode of JNK-signaling, autocrine pro-apoptotic signaling and paracrine pro-proliferative signaling, led to opposite effects in the two compartments and reprogramming of the adult wing structure. We establish Bab2 as a regulator of wing disc development, with the capacity to reprogram development via JNK activation in a cell-autonomous and non-cell-autonomous manner.Summary statementZhao et al. shows that the BTB/POZ transcription factor Bab2 is a potent activator of JNK signaling, apoptosis and compensatory proliferation, thereby driving both pro-tumorigenic and anti-tumorigenic processes.

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Ionizing radiation induces stem cell-like properties in a caspase-dependent manner in Drosophila

10.1101/316497 ◽

2018 ◽

Author(s):

Shilpi Verghese ◽

Tin Tin Su

Keyword(s):

Stem Cell ◽

Ionizing Radiation ◽

Cancer Cells ◽

Wing Disc ◽

Lineage Tracing ◽

Dependent Manner ◽

Cancer Treatments ◽

Therapeutic Success ◽

Wing Discs ◽

Regenerative Cells

ABSTRACTCancer treatments including ionizing radiation (IR) can induce cancer stem cell-like properties in non-stem cancer cells, an outcome that can interfere with therapeutic success. Yet, we understand little about what consequences of IR induces stem cell like properties and why some cancer cells show this response but not others. In previous studies, we identified a pool of epithelial cells in Drosophila larval wing discs that display IR-induced stem cell-like properties. These cells are resistant to killing by IR and, after radiation damage, change fate and translocate to regenerate parts of the disc that suffered more cell death. Here, we addressed how IR exposure results in the induction of stem cell-like behavior, and found a requirement for caspase activity. Unexpectedly, this requirement was mapped to the regenerative cells, suggesting a non-apoptotic role for caspases in the induction of stem cell-like behavior. We also performed a systematic probing of different regions of the wing disc by lineage tracing, in order to identify additional pools of cells with IR-induced regenerative properties. We identified two new populations of such cells. Unlike the original pool that helps regenerate the disc, the new pools of cells undergo abnormal regeneration to produce an ectopic, supernumerary wing disc. We also identified cells that lack the ability to display IR-induced regenerative behavior. Identification of different cell populations with different IR-induced regenerative potential will allow us to probe the molecular basis for these differences in the future.AUTHOR SUMMARYIonizing Radiation (IR), alone or in combination with other therapies, is used to treat an estimated half of all cancer patients. Yet, we understand little about why some tumors cells respond to treatment while others grow back (regenerate). We identified specific pools of cells within a Drosophila organ that are capable of regeneration after damage by IR. We also identified what it is about IR damage that allows these cells to regenerate. These results help us understand how cells regenerate after IR damage and will aid in designing better therapies that involve radiation.

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HSP27 controls GATA-1 protein level during erythroid cell differentiation

Blood ◽

10.1182/blood-2009-09-241778 ◽

2010 ◽

Vol 116 (1) ◽

pp. 85-96 ◽

Cited By ~ 42

Author(s):

Aurelie de Thonel ◽

Julie Vandekerckhove ◽

David Lanneau ◽

Subramaniam Selvakumar ◽

Geneviève Courtois ◽

...

Keyword(s):

Transcription Factor ◽

Ex Vivo ◽

Apoptotic Cell ◽

Erythroid Differentiation ◽

Proteasomal Degradation ◽

Fine Tuning ◽

Erythroid Cell ◽

Dependent Manner ◽

Cellular Expression ◽

Erythroid Cell Differentiation

Abstract Heat shock protein 27 (HSP27) is a chaperone whose cellular expression increases in response to various stresses and protects the cell either by inhibiting apoptotic cell death or by promoting the ubiquitination and proteasomal degradation of specific proteins. Here, we show that globin transcription factor 1 (GATA-1) is a client protein of HSP27. In 2 models of erythroid differentiation; that is, in the human erythroleukemia cell line, K562 induced to differentiate into erythroid cells on hemin exposure and CD34+ human cells ex vivo driven to erythroid differentiation in liquid culture, depletion of HSP27 provokes an accumulation of GATA-1 and impairs terminal maturation. More specifically, we demonstrate that, in the late stages of the erythroid differentiation program, HSP27 is phosphorylated in a p38-dependent manner, enters the nucleus, binds to GATA-1, and induces its ubiquitination and proteasomal degradation, provided that the transcription factor is acetylated. We conclude that HSP27 plays a role in the fine-tuning of terminal erythroid differentiation through regulation of GATA-1 content and activity.

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Drosophila Lyra Mutations Are Gain-of-Function Mutations of senseless

Genetics ◽

10.1093/genetics/157.1.307 ◽

2001 ◽

Vol 157 (1) ◽

pp. 307-315 ◽

Cited By ~ 1

Author(s):

Riitta Nolo ◽

Lois A Abbott ◽

Hugo J Bellen

Keyword(s):

Apoptotic Cell ◽

Ectopic Expression ◽

Wing Disc ◽

Brdu Incorporation ◽

Wing Margin ◽

Aberrant Expression ◽

Severe Reduction ◽

Wing Discs ◽

Necessary And Sufficient ◽

Wing Pouch

Abstract The Lyra mutation was first described by Jerry Coyne in 1935. Lyra causes recessive pupal lethality and adult heterozygous Lyra mutants exhibit a dominant loss of the anterior and posterior wing margins. Unlike many mutations that cause loss of wing tissue (e.g., scalloped, Beadex, cut, and apterous-Xasta), Lyra wing discs do not exhibit increased necrotic or apoptotic cell death, nor do they show altered BrdU incorporation. However, during wing disc eversion, loss of the anterior and posterior wing margins is apparent. We have previously shown that senseless, a gene that is necessary and sufficient for peripheral nervous system (PNS) development, is allelic to Lyra. Here we show by several genetic criteria that Lyra alleles are neomorphic alleles of senseless that cause ectopic expression of SENSELESS in the wing pouch. Similarly, overexpression of SENSELESS in the wing disc causes loss of wing margin tissue, thereby mimicking the Lyra phenotype. Lyra mutants display aberrant expression of DELTA, VESTIGIAL, WINGLESS, and CUT. As in Lyra mutants, overexpression of SENSELESS in some areas of the wing pouch also leads to loss of WINGLESS and CUT. In summary, our data indicate that overexpression of SENSELESS causes a severe reduction in NOTCH signaling that in turn may lead to decreased transcription of several key genes required for wing development, leading to a failure in cell proliferation and loss of wing margin tissue.

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In vivo relevance of intercellular calcium signaling in Drosophila wing development

10.1101/187401 ◽

2017 ◽

Cited By ~ 2

Author(s):

Qinfeng Wu ◽

Pavel A. Brodskiy ◽

Francisco Huizar ◽

Jamison J. Jangula ◽

Cody Narciso ◽

...

Keyword(s):

Ex Vivo ◽

Wing Disc ◽

Chemical Stimulus ◽

Wing Development ◽

Dependent Manner ◽

Drosophila Wing ◽

Wing Discs ◽

Vein Patterning ◽

Dose Dependent

AbstractRecently, organ-scale intercellular Ca2+ transients (ICTs) were reported in the Drosophila wing disc. However, the functional in vivo significance of ICTs remains largely unknown. Here we demonstrate the in vivo relevance of intercellular Ca2+ signaling and its impact on wing development. We report that Ca2+ signaling in vivo decreases as wing discs mature. Ca2+ signaling ex vivo responds to fly extract in a dose-dependent manner. This suggests ICTs occur in vivo due to chemical stimulus that varies in concentration during development. RNAi mediated inhibition of genes required for ICTs results in defects in the size, shape, and vein patterning of adult wings. It also leads to reduction or elimination of in vivo Ca2+ transients. Further, perturbations to the extracellular matrix along the basal side of the wing disc stimulates intercellular Ca2+ waves. This is the first identified chemically defined, non-wounding stimulus of ICTs. Together, these results point toward specific in vivo functions of intercellular Ca2+ signaling to mediate mechanical stress dissipation and ensure robust patterning during development.

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The spalt gene links the A/P compartment boundary to a linear adult structure in the Drosophila wing

Development ◽

10.1242/dev.124.1.21 ◽

1997 ◽

Vol 124 (1) ◽

pp. 21-32 ◽

Cited By ~ 15

Author(s):

M.A. Sturtevant ◽

B. Biehs ◽

E. Marin ◽

E. Bier

Keyword(s):

Wing Disc ◽

Posterior Compartment ◽

Expression Domain ◽

Anterior Edge ◽

Compartment Boundary ◽

Expression Of Genes ◽

Wing Discs ◽

Narrow Stripe ◽

Hedgehog Signal ◽

Anterior Posterior

During Drosophila embryogenesis, each segment is subdivided into an anterior and a posterior compartment through the action of the engrailed gene. Compartmental boundaries bisect imaginal disc primordia which give rise to adult appendages. In early larval development, a short-range Hedgehog signal originating from the posterior compartment of the imaginal wing disc activates expression of genes including decapentaplegic (dpp) in a stripe running along the anterior-posterior compartment boundary. Secreted Dpp emanating from the A/P boundary of wing discs then acts as a secondary signal to organize the wing over large distances. The transcription factor encoded by spalt major (salm) gene, which is expressed in a broad wedge centered over the dpp stripe, is one target of Dpp signaling. In this manuscript, we show that the anterior edge of the salm expression domain abuts a narrow stripe of rhomboid (rho)-expressing cells corresponding to the L2 longitudinal vein primordium. hh mis-expression along the anterior wing margin induces a surrounding domain of salm expression, the anterior edge of which abuts a displaced rho L2 stripe. salm plays a key role in defining the position of the L2 vein since loss of salm function in mosaic patches induces the formation of ectopic L2 branches, which comprise salm- cells running along clone borders where salm- cells confront salm+ cells. These data suggest that salm determines the position of the L2 vein primordium by activating rho expression in neighboring cells through a locally non-autonomous mechanism. rho then functions to initiate and maintain vein differentiation. We discuss how these data provide the final link connecting the formation of a linear adult structure to the establishment of a boundary by the maternal Bicoid morphogen gradient in the blastoderm embryo.

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DNA-binding activity of the transcription factor upstream stimulatory factor 1 (USF-1) is regulated by cyclin-dependent phosphorylation

Biochemical Journal ◽

10.1042/bj3440145 ◽

1999 ◽

Vol 344 (1) ◽

pp. 145-152 ◽

Cited By ~ 24

Author(s):

Edwin CHEUNG ◽

Petra MAYR ◽

Federico CODA-ZABETTA ◽

Phillip G. WOODMAN ◽

David S. W. BOAM

Keyword(s):

Transcription Factor ◽

Dna Binding ◽

Cellular Proliferation ◽

Phosphorylation Site ◽

Cyclin B1 ◽

Binding Activity ◽

Dependent Manner ◽

Upstream Stimulatory Factor ◽

Dna Binding Activity ◽

Stimulatory Factor

The ubiquitous transcription factor upstream stimulatory factor (USF) 1 is a member of the bzHLH (leucine zipper-basic-helix-loop-helix) family, which is structurally related to the Myc family of proteins. It plays a role in the regulation of many genes, including the cyclin B1 gene, which is active during the G2/M and M phases of the cell cycle and may also play a role in the regulation of cellular proliferation. We show that the affinity of recombinant USF-1 for DNA is greatly increased by treatment with active cyclin A2-p34cdc2 or cyclin B1-p34cdc2 complexes and that its interaction with DNA is dependent on p34cdc2-mediated phosphorylation. We have localized the phosphorylation site(s) to a region that lies outside the minimal DNA-binding domain but overlaps with the previously identified USF-specific region. Deletion studies of USF-1 suggest that amino acids 143-197 regulate DNA-binding activity in a phosphorylation-dependent manner.

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Quantitative EM of gap junction distribution in mutant drosophila wing discs

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100077177 ◽

1983 ◽

Vol 41 ◽

pp. 720-721

Author(s):

J.S. Ryerse

Keyword(s):

Gap Junctions ◽

Growth Control ◽

Intercellular Junctions ◽

Wing Disc ◽

En Bloc ◽

Metabolic Cooperation ◽

Drosophila Wing ◽

Adult Wing ◽

Wing Discs ◽

Wing Pouch

Gap junctions are intercellular junctions found in both vertebrates and invertebrates through which ions and small molecules can pass. Their distribution in tissues could be of critical importance for ionic coupling or metabolic cooperation between cells or for regulating the intracellular movement of growth control and pattern formation factors. Studies of the distribution of gap junctions in mutants which develop abnormally may shed light upon their role in normal development. I report here the distribution of gap junctions in the wing pouch of 3 Drosophila wing disc mutants, vg (vestigial) a cell death mutant, 1(2)gd (lethal giant disc) a pattern abnormality mutant and 1(2)gl (lethal giant larva) a neoplastic mutant and compare these with wildtype wing discs.The wing pouch (the anlagen of the adult wing blade) of a wild-type wing disc is shown in Fig. 1 and consists of columnar cells (Fig. 5) joined by gap junctions (Fig. 6). 14000x EMs of conventionally processed, UA en bloc stained, longitudinally sectioned wing pouches were enlarged to 45000x with a projector and tracings were made on which the lateral plasma membrane (LPM) and gap junctions were marked.

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The KLF6 Super Enhancer Modulates Cell Proliferation via MiR-1301 in Human Hepatoma Cells

MicroRNA ◽

10.2174/2211536608666190314122725 ◽

2019 ◽

Vol 9 (1) ◽

pp. 64-69 ◽

Cited By ~ 1

Author(s):

KumChol Ri ◽

Chol Kim ◽

CholJin Pak ◽

PhyongChol Ri ◽

HyonChol Om

Keyword(s):

Cell Proliferation ◽

Cellular Proliferation ◽

Hepatoma Cells ◽

Regulation Mechanism ◽

Dependent Manner ◽

Human Hepatoma ◽

Human Hepatoma Cells ◽

Over Expression ◽

Super Enhancer ◽

Engineering Changes

Background: Recent studies have attempted to elucidate the function of super enhancers by means of microRNAs. Although the functional outcomes of miR-1301 have become clearer, the pathways that regulate the expressions of miR-1301 remain unclear. Objective: The objective of this paper was to consider the pathway regulating expression of miR- 1301 and miR-1301 signaling pathways with the inhibition of cell proliferation. Methods: In this study, we prepared the cell clones that the KLF6 super enhancer was deleted by means of the CRISPR/Cas9 system-mediated genetic engineering. Changes in miR-1301 expression after the deletion of the KLF6 super enhancer were evaluated by RT-PCR analysis, and the signal pathway of miR-1301 with inhibition of the cell proliferation was examined using RNA interference technology. Results: The results showed that miR-1301 expression was significantly increased after the deletion of the KLF6 super enhancer. Over-expression of miR-1301 induced by deletion of the KLF6 super enhancer also regulated the expression of p21 and p53 in human hepatoma cells. functional modeling of findings using siRNA specific to miR-1301 showed that expression level changes had direct biological effects on cellular proliferation in Human hepatoma cells. Furthermore, cellular proliferation assay was shown to be directly associated with miR-1301 levels. Conclusion: As a result, it was demonstrated that the over-expression of miR-1301 induced by the disruption of the KLF6 super enhancer leads to a significant inhibition of proliferation in HepG2 cells. Moreover, it was demonstrated that the KLF6 super enhancer regulates the cell-proliferative effects which are mediated, at least in part, by the induction of p21and p53 in a p53-dependent manner. Our results provide the functional significance of miR-1301 in understanding the transcriptional regulation mechanism of the KLF6 super enhancer.

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Colorectal Cancer Apoptosis Induced by Dietary δ-Valerobetaine Involves PINK1/Parkin Dependent-Mitophagy and SIRT3

International Journal of Molecular Sciences ◽

10.3390/ijms22158117 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8117

Author(s):

Nunzia D’Onofrio ◽

Elisa Martino ◽

Luigi Mele ◽

Antonino Colloca ◽

Martina Maione ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Mitochondrial Dysfunction ◽

Cancer Cells ◽

Current Knowledge ◽

Apoptotic Cell ◽

Critical Role ◽

Dependent Manner ◽

Colon Cancer Cells ◽

Protein Levels

Understanding the mechanisms of colorectal cancer progression is crucial in the setting of strategies for its prevention. δ-Valerobetaine (δVB) is an emerging dietary metabolite showing cytotoxic activity in colon cancer cells via autophagy and apoptosis. Here, we aimed to deepen current knowledge on the mechanism of δVB-induced colon cancer cell death by investigating the apoptotic cascade in colorectal adenocarcinoma SW480 and SW620 cells and evaluating the molecular players of mitochondrial dysfunction. Results indicated that δVB reduced cell viability in a time-dependent manner, reaching IC50 after 72 h of incubation with δVB 1.5 mM, and caused a G2/M cell cycle arrest with upregulation of cyclin A and cyclin B protein levels. The increased apoptotic cell rate occurred via caspase-3 activation with a concomitant loss in mitochondrial membrane potential and SIRT3 downregulation. Functional studies indicated that δVB activated mitochondrial apoptosis through PINK1/Parkin pathways, as upregulation of PINK1, Parkin, and LC3B protein levels was observed (p < 0.0001). Together, these findings support a critical role of PINK1/Parkin-mediated mitophagy in mitochondrial dysfunction and apoptosis induced by δVB in SW480 and SW620 colon cancer cells.

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Targeting BMI-1 with PLGA–PEG nanoparticle-containing PTC209 modulates the behavior of human glioblastoma stem cells and cancer cells

Cancer Nanotechnology ◽

10.1186/s12645-021-00078-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Elham Poonaki ◽

Fatemeh Ariakia ◽

Mohammad Jalili-Nik ◽

Mehdi Shafiee Ardestani ◽

Gholamhossein Tondro ◽

...

Keyword(s):

Drug Loading ◽

Polycomb Group ◽

Dependent Manner ◽

Migration Ability ◽

Jnk Signaling ◽

Human Glioblastoma ◽

Core Member ◽

Ic50 Values ◽

Human Gbm ◽

Dose Dependent

AbstractDespite advances in glioblastoma (GBM) treatments, current approaches have failed to improve the overall survival of patients. The oncogene BMI-1, a core member of the polycomb group proteins, is a potential novel therapeutic target for GBM. To enhance the efficacy and reduce the toxicity, PTC209, a BMI-1 inhibitor, was loaded into a PLGA–PEG nanoparticle conjugated with CD133 antibody (Nano-PTC209) and its effect on the behavior of human GBM stem-like cells (GSCs) and the human glioblastoma cell line (U87MG) was assessed. Nano-PTC209 has a diameter of ~ 75 nm with efficient drug loading and controlled release. The IC50 values of Nano-PTC209 for GSCs and U87MG cells were considerably lower than PTC209. Nano-PTC209 significantly decreased the viability of both GSCs and U87MG cells in a dose-dependent manner and caused a significant enhancement of apoptosis and p53 levels as well as inhibition of AKT and JNK signaling pathways. Furthermore, Nano-PTC209 significantly inhibited the migration ability, decreased the activity of metalloproteinase-2 and -9, and increased the generation of reactive oxygen species in both GSCs and U87MG cells. Our data indicate that PLGA–PEG nanoparticle conjugated with CD133 antibody could be an ideal nanocarrier to deliver PTC209 and effectively target BMI-1 for potential approaches in the treatment of GBM.

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