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1.
Development ; 148(14)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34313318

RESUMO

Heterozygosity of ribosomal protein genes causes a variety of developmental abnormalities in humans, which are collectively known as ribosomopathies, yet the underlying mechanisms remain elusive. Here, we analyzed Drosophila Minute (M)/+ mutants, a group of mutants heterozygous for ribosomal protein genes that exhibit a characteristic thin-bristle phenotype. We found that, although M/+ flies develop essentially normal wings, simultaneous deletion of one copy of the Hippo pathway effector yki resulted in severe wing growth defects. These defects were caused by JNK-mediated cell death in the wing pouch via Eiger/TNF signaling. The JNK activation in M/+, yki/+ wing discs required the caspase Dronc, which is normally blocked by DIAP1. Notably, heterozygosity of yki reduced DIAP1 expression in the wing pouch, leading to elevation of Dronc activity. Dronc and JNK formed a positive-feedback loop that amplifies Dronc activation, leading to apoptosis. Our observations suggest a mechanism of robust tissue growth whereby tissues with reduced ribosomal protein prevent ectopic apoptosis via Yki activity.


Assuntos
Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Animais , Apoptose , Morte Celular , Regulação para Baixo , Drosophila/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Inibidoras de Apoptose/metabolismo , Proteínas Nucleares/genética , Transdução de Sinais , Transativadores/genética , Asas de Animais/anatomia & histologia , Asas de Animais/metabolismo
2.
PLoS Genet ; 17(1): e1009300, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33507966

RESUMO

Highly reproducible tissue development is achieved by robust, time-dependent coordination of cell proliferation and cell death. To study the mechanisms underlying robust tissue growth, we analyzed the developmental process of wing imaginal discs in Drosophila Minute mutants, a series of heterozygous mutants for a ribosomal protein gene. Minute animals show significant developmental delay during the larval period but develop into essentially normal flies, suggesting there exists a mechanism ensuring robust tissue growth during abnormally prolonged developmental time. Surprisingly, we found that both cell death and compensatory cell proliferation were dramatically increased in developing wing pouches of Minute animals. Blocking the cell-turnover by inhibiting cell death resulted in morphological defects, indicating the essential role of cell-turnover in Minute wing morphogenesis. Our analyses showed that Minute wing discs elevate Wg expression and JNK-mediated Dilp8 expression that causes developmental delay, both of which are necessary for the induction of cell-turnover. Furthermore, forced increase in Wg expression together with developmental delay caused by ecdysone depletion induced cell-turnover in the wing pouches of non-Minute animals. Our findings suggest a novel paradigm for robust coordination of tissue growth by cell-turnover, which is induced when developmental time axis is distorted.


Assuntos
Proteínas de Drosophila/genética , Discos Imaginais/crescimento & desenvolvimento , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas Ribossômicas/genética , Proteína Wnt1/genética , Animais , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Ecdisona/genética , Células Epiteliais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Discos Imaginais/metabolismo , Larva/genética , Larva/crescimento & desenvolvimento , Metamorfose Biológica/genética , Organogênese/genética , Transdução de Sinais/genética , Fatores de Transcrição/genética , Asas de Animais/crescimento & desenvolvimento , Asas de Animais/metabolismo
3.
Sci Rep ; 9(1): 19549, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31863086

RESUMO

Multicellular organisms repair injured epithelium by evolutionarily conserved biological processes including activation of c-Jun N-terminal kinase (JNK) signaling. Here, we show in Drosophila imaginal epithelium that physical injury leads to the emergence of dying cells, which are extruded from the wounded tissue by JNK-induced Slit-Roundabout2 (Robo2) repulsive signaling. Reducing Slit-Robo2 signaling in the wounded tissue suppresses extrusion of dying cells and generates aberrant cells with highly upregulated growth factors Wingless (Wg) and Decapentaplegic (Dpp). The inappropriately elevated Wg and Dpp impairs wound repair, as halving one of these growth factor genes cancelled wound healing defects caused by Slit-Robo2 downregulation. Our data suggest that JNK-mediated Slit-Robo2 signaling contributes to epithelial wound repair by promoting extrusion of dying cells from the wounded tissue, which facilitates transient and appropriate induction of growth factors for proper wound healing.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Transdução de Sinais/fisiologia , Animais , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Proteína Wnt1/genética , Proteína Wnt1/metabolismo , Cicatrização/genética , Cicatrização/fisiologia
4.
Dev Growth Differ ; 61(5): 337-342, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30957223

RESUMO

Normal epithelial tissues often put anti-tumorigenic pressure on newly emerged oncogenic cells through cell-cell communications. In Drosophila epithelium, clones of oncogenic cells mutant for evolutionarily conserved apico-basal polarity genes such as scribble (scrib) and discs large (dlg) are actively eliminated when surrounded by normal cells. It has been reported that c-Jun N-terminal kinase (JNK) signaling in polarity-deficient cells is crucial for their cell death. However, the mechanism by which normal epithelial tissues exert anti-tumorigenic effects on polarity-deficient cells had been elusive. Here, I describe our genetic studies in Drosophila epithelium especially focused on the role of surrounding normal epithelial cells in response to the emergence of polarity-deficient cells. Furthermore, I also describe recent studies regarding the mechanism by which polarity-deficient cells are extruded from the tissue, and discuss future perspectives on the study of cell-cell communications in epithelial homeostasis.


Assuntos
Drosophila/citologia , Células Epiteliais/citologia , Células Epiteliais/patologia , Homeostase , Animais , Drosophila/genética , Células Epiteliais/metabolismo , Homeostase/genética
5.
Curr Biol ; 28(13): 2115-2128.e5, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29910075

RESUMO

During the initial stage of tumor progression, oncogenic cells spread despite spatial confinement imposed by surrounding normal tissue. This spread of oncogenic cells (winners) is thought to be governed by selective killing of surrounding normal cells (losers) through a phenomenon called "cell competition" (i.e., supercompetition). Although the mechanisms underlying loser elimination are increasingly apparent, it is not clear how winner cells selectively occupy the space made available following loser apoptosis. Here, we combined live imaging analyses of two different oncogenic clones (Yki/YAP activation and Ras activation) in the Drosophila epithelium with computer simulation of tissue mechanics to elucidate such a mechanism. Contrary to the previous expectation that cell volume loss after apoptosis of loser cells was simply compensated for by the faster proliferation of winner cells, we found that the lost volume was compensated for by rapid cell expansion of winners. Mechanistically, the rapid winner-dominated cell expansion was driven by apoptosis-induced epithelial junction remodeling, which causes re-connection of local cellular connectivity (cell topology) in a manner that selectively increases winner apical surface area. In silico experiments further confirmed that repetition of loser elimination accelerates tissue-scale winner expansion through topological changes over time. Our proposed mechanism for linking loser death and winner expansion provides a new perspective on how tissue homeostasis disruption can initiate from an oncogenic mutation.


Assuntos
Apoptose/fisiologia , Proliferação de Células/fisiologia , Drosophila melanogaster/fisiologia , Células Epiteliais/fisiologia , Transdução de Sinais/fisiologia , Animais , Fenômenos Biomecânicos , Simulação por Computador , Homeostase
6.
Curr Biol ; 28(11): 1756-1767.e6, 2018 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-29804808

RESUMO

Normal epithelial tissue exerts an intrinsic tumor-suppressive effect against oncogenically transformed cells. In Drosophila imaginal epithelium, clones of oncogenic polarity-deficient cells mutant for scribble (scrib) or discs large (dlg) are eliminated by cell competition when surrounded by wild-type cells. Here, through a genetic screen in Drosophila, we identify Serpin5 (Spn5), a secreted negative regulator of Toll signaling, as a crucial factor for epithelial cells to eliminate scrib mutant clones from epithelium. Downregulation of Spn5 in wild-type cells leads to elevation of Toll signaling in neighboring scrib cells. Strikingly, forced activation of Toll signaling or Toll-related receptor (TRR) signaling in scrib clones transforms scrib cells from losers to supercompetitors, resulting in tumorous overgrowth of mutant clones. Mechanistically, Toll activation in scrib clones leads to c-Jun N-terminal kinase (JNK) activation and F-actin accumulation, which cause strong activation of the Hippo pathway effector Yorkie that blocks cell death and promotes cell proliferation. Our data suggest that Spn5 secreted from normal epithelial cells acts as a component of the extracellular surveillance system that facilitates elimination of pre-malignant cells from epithelium.


Assuntos
Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Regulação da Expressão Gênica/fisiologia , Serpinas/genética , Transdução de Sinais/genética , Receptores Toll-Like/fisiologia , Animais , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Células Epiteliais/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Serpinas/metabolismo , Receptores Toll-Like/genética , Transativadores/genética , Transativadores/metabolismo
7.
Oncogene ; 37(23): 3088-3097, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29535423

RESUMO

Epithelial cancer tissues often possess polyploid giant cells, which are thought to be highly oncogenic. However, the mechanisms by which polyploid giant cells are generated in tumor tissues and how such cells contribute to tumor progression remain elusive. We previously noticed in Drosophila imaginal epithelium that cells mutant for the endocytic gene rab5 exhibit enlarged nuclei. Here we find that mutations in endocytic 'neoplastic tumor-suppressor' genes, such as rab5, vps25, erupted, or avalanche result in generation of polyploid giant cells. Genetic analyses on rab5-defective cells reveal that cooperative activation of JNK and Yorkie generates polyploid giant cells via endoreplication. Mechanistically, Yorkie-mediated upregulation of Diap1 cooperates with JNK to downregulate the G2/M cyclin CycB, thereby inducing endoreplication. Interestingly, malignant tumors induced by Ras activation and cell polarity defect also consist of polyploid giant cells, which are generated by JNK and Yorkie-mediated downregulation of CycB. Strikingly, elimination of polyploid giant cells from such malignant tumors by blocking endoreplication strongly suppressed tumor growth and metastatic behavior. Our observations suggest that JNK and Yorkie, two oncogenic proteins activated in many types of human cancers, cooperatively drive tumor progression by generating oncogenic polyploid giant cells.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/patogenicidade , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Nucleares/metabolismo , Poliploidia , Transativadores/metabolismo , Animais , Animais Geneticamente Modificados , Ciclina B/genética , Ciclina B/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Regulação da Expressão Gênica , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Proteínas Nucleares/genética , Transativadores/genética , Proteínas rab5 de Ligação ao GTP/genética , Proteínas rab5 de Ligação ao GTP/metabolismo
9.
Genes Cells ; 23(3): 234-240, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29431244

RESUMO

Cells heterozygously mutant for a ribosomal protein gene, called Minute/+ mutants, are eliminated from epithelium by cell competition when surrounded by wild-type cells. Whereas several factors that regulate Minute cell competition have been identified, the mechanisms how winner/loser status is determined and thereby triggers cell competition are still elusive. To address this, we established two assay systems for Minute cell competition, namely (i) the CORE (competitive elimination of RpS3-RNAi-expressing cells) system in which RpS3-RNAi-expressing wing pouch cells are eliminated from wild-type wing disc and (ii) the SURE (supercompetition of RpS3-expressing clones in RpS3/+ tissue) system in which RpS3-over-expressing clones generated in RpS3/+ wing disc outcompete surrounding RpS3/+ cells. An ectopic over-expression screen using the CORE system identified Wg signaling as a critical regulator of Minute cell competition. Activation of Wg signaling in loser cells suppressed their elimination, whereas down-regulation of Wg signaling in loser cells enhanced their elimination. Furthermore, using the SURE system, we found that down-regulation of Wg signaling in winner cells suppressed elimination of neighboring losers. Our observations suggest that cellular Wg signaling activity is crucial for determining winner/loser status and thereby triggering Minute cell competition.


Assuntos
Drosophila melanogaster/crescimento & desenvolvimento , Transdução de Sinais , Animais , Animais Geneticamente Modificados/crescimento & desenvolvimento , Animais Geneticamente Modificados/fisiologia , Apoptose , Comunicação Celular , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Ribossômicas/genética , Proteínas Ribossômicas/metabolismo , Proteína Wnt1/genética , Proteína Wnt1/metabolismo
10.
Dev Cell ; 44(3): 284-296, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29408235

RESUMO

Epithelial tissues robustly respond to internal and external stressors via dynamic cellular rearrangements. Cell extrusion acts as a key regulator of epithelial homeostasis by removing apoptotic cells, orchestrating morphogenesis, and mediating competitive cellular battles during tumorigenesis. Here, we delineate the diverse functions of cell extrusion during development and disease. We emphasize the expanding role for apoptotic cell extrusion in exerting morphogenetic forces, as well as the strong intersection of cell extrusion with cell competition, a homeostatic mechanism that eliminates aberrant or unfit cells. While cell competition and extrusion can exert potent, tumor-suppressive effects, dysregulation of either critical homeostatic program can fuel cancer progression.


Assuntos
Fenômenos Fisiológicos Celulares , Células Epiteliais/fisiologia , Homeostase , Morfogênese/fisiologia , Estresse Fisiológico , Animais , Sobrevivência Celular , Células Epiteliais/citologia , Humanos
11.
Nature ; 542(7640): 246-250, 2017 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-28092921

RESUMO

Normal epithelial cells often exert anti-tumour effects against nearby oncogenic cells. In the Drosophila imaginal epithelium, clones of oncogenic cells with loss-of-function mutations in the apico-basal polarity genes scribble or discs large are actively eliminated by cell competition when surrounded by wild-type cells. Although c-Jun N-terminal kinase (JNK) signalling plays a crucial role in this cell elimination, the initial event, which occurs at the interface between normal cells and polarity-deficient cells, has not previously been identified. Here, through a genetic screen in Drosophila, we identify the ligand Sas and the receptor-type tyrosine phosphatase PTP10D as the cell-surface ligand-receptor system that drives tumour-suppressive cell competition. At the interface between the wild-type 'winner' and the polarity-deficient 'loser' clones, winner cells relocalize Sas to the lateral cell surface, whereas loser cells relocalize PTP10D there. This leads to the trans-activation of Sas-PTP10D signalling in loser cells, which restrains EGFR signalling and thereby enables elevated JNK signalling in loser cells, triggering cell elimination. In the absence of Sas-PTP10D, elevated EGFR signalling in loser cells switches the role of JNK from pro-apoptotic to pro-proliferative by inactivating the Hippo pathway, thereby driving the overgrowth of polarity-deficient cells. These findings uncover the mechanism by which normal epithelial cells recognize oncogenic polarity-deficient neighbours to drive cell competition.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Neoplasias/patologia , Proteínas Tirosina Fosfatases/metabolismo , Receptores de Superfície Celular/metabolismo , Animais , Apoptose , Polaridade Celular , Proliferação de Células , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Receptores ErbB/metabolismo , Feminino , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Ligantes , Masculino , Proteínas de Membrana/genética , Neoplasias/metabolismo , Transdução de Sinais , Ativação Transcricional , Proteínas Supressoras de Tumor/genética
12.
J Theor Biol ; 404: 40-50, 2016 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-27234645

RESUMO

The phenomenon of 'cell competition' has been implicated in the normal development and maintenance of organs, such as in the regulation of organ size and suppression of neoplastic development. In cell competition, one group of cells competes with another group through an interaction at their interface. Which cell group "wins" is governed by a certain relative fitness within the cells. However, this idea of cellular fitness has not been clearly defined. We construct two types of mathematical models to describe this phenomenon of cell competition by considering the interaction at the interface as a predator-prey type interaction in a monolayer tissue such as epithelium. Both of these models can reproduce several typical experimental observations involving systems of mutant cells (losers) and normal cells (winners). By analyzing one of the model and defining an index for the degree of fitness in groups of cells, we show that the fate of each group mainly depends on the relative carrying capacities of certain resources and the strength of the predator-prey interaction at the interface. This contradicts the classical hypothesis in which the relative proliferation rate determines the winner.


Assuntos
Células/metabolismo , Modelos Teóricos , Movimento Celular , Proliferação de Células , Mutação/genética
13.
Dev Biol ; 403(2): 162-71, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25967126

RESUMO

The c-Jun N-terminal kinase (JNK) pathway is a dual-functional oncogenic signaling that exerts both anti- and pro-tumor activities. However, the mechanism by which JNK switches its oncogenic roles depending on different cellular contexts has been elusive. Here, using the Drosophila genetics, we show that hyperactive Ras acts as a signaling switch that converts JNK's role from anti- to pro-tumor signaling through the regulation of Hippo signaling activity. In the normal epithelium, JNK signaling antagonizes the Hippo pathway effector Yorkie (Yki) through elevation of Warts activity, thereby suppressing tissue growth. In contrast, in the presence of hyperactive Ras, JNK signaling enhances Yki activation by accumulating F-actin through the activity of the LIM domain protein Ajuba, thereby promoting tissue growth. We also find that the epidermal growth factor receptor (EGFR) signaling uses this Ras-mediated conversion of JNK signaling to promote tissue growth. Our observations suggest that Ras-mediated switch of the JNK pathway from anti- to pro-tumor signaling could play crucial roles in tumorigenesis as well as in normal development.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Discos Imaginais/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Quinases/metabolismo , Proteínas ras/metabolismo , Animais , Proteínas de Drosophila/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transativadores/metabolismo
14.
Nat Commun ; 5: 5264, 2014 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-25345385

RESUMO

Cell-cell interactions play important roles in epithelial tumorigenesis. Here we show in Drosophila imaginal epithelium that Ras activation and mitochondrial dysfunction, frequent alterations in cancers, cause cellular senescence and senescence-associated secretory phenotype (SASP), which leads to overgrowth of neighbouring tissue. Ras-activated cells express several hallmarks of cellular senescence such as elevation of senescence-associated ß-galactosidase activity, upregulation of the Cdk inhibitor Dacapo, heterochromatinization and cellular hypertrophy. Strikingly, defects in mitochondrial function cause Ras-activated cells to undergo DNA damage response, cell cycle arrest and thereby induce SASP, exhibiting full aspects of cellular senescence. Mechanistically, mitochondrial defects in conjunction with Ras cause production of reactive oxygen species, downregulation of CycE activity and activation of p53, which cooperate together to trigger a cell cycle arrest-Jun N-terminal kinase (JNK) feedback loop that amplifies JNK activation, leading to upregulation of the inflammatory cytokine Unpaired. Our data suggest that mitochondrial defects promote Ras-induced cellular senescence and thereby contribute to tumour progression through SASP.


Assuntos
Senescência Celular , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Mitocôndrias/metabolismo , Animais , Biomarcadores/metabolismo , Proliferação de Células , Ativação Enzimática , Olho/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular , Proteínas de Fluorescência Verde/metabolismo , Hipertrofia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases , Modelos Biológicos , Fenótipo , Proteína Supressora de Tumor p53/metabolismo , Proteínas ras/metabolismo
15.
Dev Biol ; 395(1): 19-28, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25224221

RESUMO

Deregulation of the endocytic machinery has been implicated in human cancers. However, the mechanism by which endocytic defects drive cancer development remains to be clarified. Here, we find through a genetic screen in Drosophila that loss of Rab5, a protein required for early endocytic trafficking, drives non-autonomous cell proliferation in imaginal epithelium. Our genetic data indicate that dysfunction of Rab5 leads to cell-autonomous accumulation of Eiger (a TNF homolog) and EGF receptor (EGFR), which causes activation of downstream JNK and Ras signaling, respectively. JNK signaling and its downstream component Cdc42 cooperate with Ras signaling to induce upregulation of a secreted growth factor Upd (an IL-6 homolog) through inactivation of the Hippo pathway. Such non-autonomous tissue growth triggered by Rab5 defect could contribute to epithelial homeostasis as well as cancer development within heterogeneous tumor microenvironment.


Assuntos
Proliferação de Células , Proteínas de Drosophila/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Proteínas rab5 de Ligação ao GTP/metabolismo , Proteínas ras/metabolismo , Animais , Animais Geneticamente Modificados , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Olho/metabolismo , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Discos Imaginais/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Microscopia Confocal , Modelos Biológicos , Modelos Genéticos , Mutação , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fator de Necrose Tumoral alfa/genética , Proteínas rab5 de Ligação ao GTP/genética , Proteínas ras/genética
16.
J Biochem ; 156(3): 129-36, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25012819

RESUMO

Cancers develop through sequential acquisition of oncogenic mutations, indicating a crucial role of genetic alterations in tumour progression. However, accumulating evidence suggests that cancers also progress towards malignancy through cell-cell interactions within heterogeneous tumour tissue. Recent studies have indicated that tumour heterogeneity not only contributes to drug resistance and tumour recurrence but also plays an active role in promoting tumour progression. Especially, genetic studies in Drosophila have discovered novel types of tumour progression through cell-cell interactions and have dissected the underlying mechanisms. This review focuses on describing recent findings obtained from Drosophila genetics that provide genetic basis of interclonal oncogenic cooperation in heterogeneous tumour tissue.


Assuntos
Drosophila/genética , Heterogeneidade Genética , Mutação , Neoplasias/genética , Animais , Transformação Celular Neoplásica/genética , Evolução Clonal/genética , Proteínas de Drosophila/genética , Modelos Genéticos , Neoplasias/patologia , Proteínas Proto-Oncogênicas/genética
17.
Nature ; 490(7421): 547-51, 2012 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-23023132

RESUMO

Mitochondrial respiratory function is frequently impaired in human cancers. However, the mechanisms by which mitochondrial dysfunction contributes to tumour progression remain elusive. Here we show in Drosophila imaginal epithelium that defects in mitochondrial function potently induce tumour progression of surrounding tissue in conjunction with oncogenic Ras. Our data show that Ras activation and mitochondrial dysfunction cooperatively stimulate production of reactive oxygen species, which causes activation of c-Jun amino (N)-terminal kinase (JNK) signalling. JNK cooperates with oncogenic Ras to inactivate the Hippo pathway, leading to upregulation of its targets Unpaired (an interleukin-6 homologue) and Wingless (a Wnt homologue). Mitochondrial dysfunction in Ras-activated cells further cooperates with Ras signalling in neighbouring cells with normal mitochondrial function, causing benign tumours to exhibit metastatic behaviour. Our findings provide a mechanistic basis for interclonal tumour progression driven by mitochondrial dysfunction and oncogenic Ras.


Assuntos
Progressão da Doença , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mitocôndrias/patologia , Neoplasias/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Animais , Transformação Celular Neoplásica , Células Clonais/metabolismo , Células Clonais/patologia , Olho Composto de Artrópodes/crescimento & desenvolvimento , Olho Composto de Artrópodes/patologia , Olho Composto de Artrópodes/ultraestrutura , Modelos Animais de Doenças , Drosophila melanogaster/enzimologia , Drosophila melanogaster/genética , Discos Imaginais/metabolismo , Discos Imaginais/patologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Proteína Oncogênica p21(ras)/genética , Proteína Oncogênica p21(ras)/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Fatores de Transcrição/metabolismo , Regulação para Cima , Proteína Wnt1/metabolismo
18.
Methods Enzymol ; 506: 407-13, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22341235

RESUMO

Cell competition is a process in which cells with higher fitness ("winners") survive and proliferate at the expense of less fit neighbors ("losers"). It has been suggested that cell competition is involved in a variety of biological processes such as organ size control, tissue homeostasis, cancer progression, and the maintenance of stem cell population. By advent of a genetic mosaic technique, which enables to generate fluorescently marked somatic clones in Drosophila imaginal discs, recent studies have presented some aspects of molecular mechanisms underlying cell competition. Now, with a live-imaging technique using ex vivo-cultured imaginal discs, we can dissect the spatiotemporal nature of competitive cell behaviors within multicellular communities. Here, we describe procedures and tips for live imaging of cell competition in Drosophila imaginal discs.


Assuntos
Drosophila/ultraestrutura , Discos Imaginais/citologia , Discos Imaginais/ultraestrutura , Microscopia Confocal/métodos , Animais , Comunicação Celular , Técnicas de Cultura de Células , Sobrevivência Celular , Células Cultivadas , Drosophila/citologia
19.
Dev Cell ; 20(3): 315-28, 2011 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-21397843

RESUMO

A newly emerged oncogenic cell in the epithelial population has to confront antitumor selective pressures in the host tissue. However, the mechanisms by which surrounding normal tissue exerts antitumor effects against oncogenically transformed cells are poorly understood. In Drosophila imaginal epithelia, clones of cells mutant for evolutionarily conserved tumor suppressor genes such as scrib or dlg lose their epithelial integrity and are eliminated from epithelia when surrounded by wild-type tissue. Here, we show that surrounding normal cells activate nonapoptotic JNK signaling in response to the emergence of oncogenic mutant cells. This JNK activation leads to upregulation of PVR, the Drosophila PDGF/VEGF receptor. Genetic and time-lapse imaging analyses reveal that PVR expression in surrounding cells activates the ELMO/Mbc-mediated phagocytic pathway, thereby eliminating oncogenic neighbors by engulfment. Our data indicate that JNK-mediated cell engulfment could be an evolutionarily conserved intrinsic tumor-suppression mechanism that eliminates premalignant cells from epithelia.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/anatomia & histologia , Drosophila melanogaster/embriologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Oncogenes , Fagocitose/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Ativação Enzimática , Epitélio/embriologia , Epitélio/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neoplasias/patologia , Neoplasias/fisiopatologia , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais/fisiologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
20.
Proc Natl Acad Sci U S A ; 107(30): 13366-71, 2010 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-20624980

RESUMO

Although the apoptotic role of caspases has been largely understood, accumulating evidence in Drosophila suggests that caspases also control other processes than apoptotic cell death. However, how caspases contribute to the development of the mammalian nervous system remains obscure. Here, we provide unique evidence that Apaf-1/caspase-9-mediated caspase signaling regulates the development of olfactory sensory neurons (OSNs), which includes axonal projection, synapse formation, and maturation of these neurons. This caspase signaling leads to a cleavage of Semaphorin 7A, a membrane-anchored semaphorin that is required for the proper axonal projection. Mutant mice deficient for apaf-1 or caspase-9 exhibit misrouted axons, impaired synaptic formation, and defects in the maturation of OSNs without affecting the number of these cells. Our findings suggest that Apaf-1/caspase-9-mediated nonapoptotic caspase signaling is required for the proper neural network formation during olfactory development.


Assuntos
Fator Apoptótico 1 Ativador de Proteases/metabolismo , Caspase 9/metabolismo , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais/fisiologia , Animais , Apoptose/fisiologia , Fator Apoptótico 1 Ativador de Proteases/genética , Axônios/fisiologia , Caspase 3/metabolismo , Caspase 9/genética , Linhagem Celular Tumoral , Mesângio Glomerular/anormalidades , Mesângio Glomerular/metabolismo , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Condutos Olfatórios/citologia , Condutos Olfatórios/embriologia , Condutos Olfatórios/crescimento & desenvolvimento , Semaforinas/metabolismo , Células Receptoras Sensoriais/citologia , Sinapses/fisiologia , Fatores de Tempo
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