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1.
Int J Mol Sci ; 20(18)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31540349

RESUMO

Alterations from the normal set of chromosomes are extremely common as cells progress toward tumourigenesis. Similarly, we expect to see disruption of normal cellular metabolism, particularly in the use of glucose. In this review, we discuss the connections between these two processes: how chromosomal aberrations lead to metabolic disruption, and vice versa. Both processes typically result in the production of elevated levels of reactive oxygen species, so we particularly focus on their role in mediating oncogenic changes.


Assuntos
Aneuploidia , Carcinogênese/genética , Carcinogênese/metabolismo , Glicólise , Estresse Oxidativo , Animais , Carcinogênese/patologia , Aberrações Cromossômicas , Dano ao DNA , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Espécies Reativas de Oxigênio/metabolismo
2.
Genes Chromosomes Cancer ; 54(12): 745-61, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26390919

RESUMO

Fragile site FRA16D exhibits DNA instability in cancer, resulting in diminished levels of protein from the WWOX gene that spans it. WWOX suppresses tumor growth by an undefined mechanism. WWOX participates in pathways involving aerobic metabolism and reactive oxygen species. WWOX comprises two WW domains as well as a short-chain dehydrogenase/reductase enzyme. Herein is described an in vivo genetic analysis in Drosophila melanogaster to identify functional interactions between WWOX and metabolic pathways. Altered WWOX levels modulate variable cellular outgrowths caused by genetic deficiencies of components of the mitochondrial respiratory complexes. This modulation requires the enzyme active site of WWOX, and the defective respiratory complex-induced cellular outgrowths are mediated by reactive oxygen species, dependent upon the Akt pathway and sensitive to levels of autophagy and hypoxia-inducible factor. WWOX is known to contribute to homeostasis by regulating the balance between oxidative phosphorylation and glycolysis. Reduction of WWOX levels results in diminished ability to respond to metabolic perturbation of normal cell growth. Thus, the ability of WWOX to facilitate escape from mitochondrial damage-induced glycolysis (Warburg effect) is, therefore, a plausible mechanism for its tumor suppressor activity.


Assuntos
Sítios Frágeis do Cromossomo , Proteínas de Drosophila/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Glicólise/genética , Mitocôndrias/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Domínio Catalítico , Proliferação de Células , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Homeostase , Redes e Vias Metabólicas/genética , Mitocôndrias/genética , NADH NADPH Oxirredutases/genética , NADH NADPH Oxirredutases/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Fosforilação Oxidativa , Espécies Reativas de Oxigênio/metabolismo , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW
3.
J Mol Neurosci ; 74(2): 50, 2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38693434

RESUMO

Aneuploidy, having an aberrant genome, is gaining increasing attention in neurodegenerative diseases. It gives rise to proteotoxic stress as well as a stereotypical oxidative shift which makes these cells sensitive to internal and environmental stresses. A growing body of research from numerous laboratories suggests that many neurodegenerative disorders, especially Alzheimer's disease and frontotemporal dementia, are characterised by neuronal aneuploidy and the ensuing apoptosis, which may contribute to neuronal loss. Using Drosophila as a model, we investigated the effect of induced aneuploidy in GABAergic neurons. We found an increased proportion of aneuploidy due to Mad2 depletion in the third-instar larval brain and increased cell death. Depletion of Mad2 in GABAergic neurons also gave a defective climbing and seizure phenotype. Feeding animals an antioxidant rescued the climbing and seizure phenotype. These findings suggest that increased aneuploidy leads to higher oxidative stress in GABAergic neurons which causes cell death, climbing defects, and seizure phenotype. Antioxidant feeding represents a potential therapy to reduce the aneuploidy-driven neurological phenotype.


Assuntos
Aneuploidia , Neurônios GABAérgicos , Estresse Oxidativo , Fenótipo , Animais , Neurônios GABAérgicos/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Convulsões/genética , Convulsões/metabolismo , Drosophila melanogaster/genética , Encéfalo/metabolismo , Drosophila/genética
4.
Metabolites ; 13(5)2023 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-37233683

RESUMO

Aneuploidy, or having a disrupted genome, is an aberration commonly found in tumours but rare in normal tissues. It gives rise to proteotoxic stress as well as a stereotypical oxidative shift, which makes these cells sensitive to internal and environmental stresses. Using Drosophila as a model, we investigated the changes in transcription in response to ongoing changes to ploidy (chromosomal instability, CIN). We noticed changes in genes affecting one-carbon metabolism, specifically those affecting the production and use of s-adenosyl methionine (SAM). The depletion of several of these genes has led to cell death by apoptosis in CIN cells but not in normal proliferating cells. We found that CIN cells are particularly sensitive to SAM metabolism at least partly because of its role in generating polyamines. Feeding animals spermine was seen to rescue the cell death caused by the loss of SAM synthase in CIN tissues. The loss of polyamines led to decreased rates of autophagy and sensitivity to reactive oxygen species (ROS), which we have shown to contribute significantly to cell death in CIN cells. These findings suggest that a well-tolerated metabolic intervention such as polyamine inhibition has the potential to target CIN tumours via a relatively well-characterised mechanism.

5.
Biomolecules ; 12(12)2022 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-36551330

RESUMO

Cancer metabolic reprogramming is essential for maintaining cancer cell survival and rapid replication. A common target of this metabolic reprogramming is one-carbon metabolism which is notable for its function in DNA synthesis, protein and DNA methylation, and antioxidant production. Polyamines are a key output of one-carbon metabolism with widespread effects on gene expression and signaling. As a result of these functions, one-carbon and polyamine metabolism have recently drawn a lot of interest for their part in cancer malignancy. Therapeutic inhibitors that target one-carbon and polyamine metabolism have thus been trialed as anticancer medications. The significance and future possibilities of one-carbon and polyamine metabolism as a target in cancer therapy are discussed in this review.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Carbono/metabolismo , Poliaminas/metabolismo , Metilação de DNA , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo
6.
J Biol Chem ; 285(37): 28667-73, 2010 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-20628062

RESUMO

The assembly and constriction of an actomyosin contractile ring in cytokinesis is dependent on the activation of Rho at the equatorial cortex by a complex, here termed the cytokinesis initiation complex, between a microtubule-associated kinesin-like protein (KLP), a member of the RacGAP family, and the RhoGEF Pebble. Recently, the activity of the mammalian Polo kinase ortholog Plk1 has been implicated in the formation of this complex. We show here that Polo kinase interacts directly with the cytokinesis initiation complex by binding RacGAP50C. We find that a new domain of Polo kinase, termed the intermediate domain, interacts directly with RacGAP50C and that Polo kinase is essential for localization of the KLP-RacGAP centralspindlin complex to the cell equator and spindle midzone. In the absence of Polo kinase, RacGAP50C and Pav-KLP fail to localize normally, instead decorating microtubules along their length. Our results indicate that Polo kinase directly binds the conserved cytokinesis initiation complex and is required to trigger centralspindlin localization as a first step in cytokinesis.


Assuntos
Citocinese/fisiologia , Proteínas de Drosophila/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Fuso Acromático/metabolismo , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster , Proteínas Ativadoras de GTPase/genética , Cinesinas/genética , Cinesinas/metabolismo , Complexos Multiproteicos/genética , Ligação Proteica , Proteínas Serina-Treonina Quinases/genética , Estrutura Terciária de Proteína , Fuso Acromático/genética
7.
Curr Biol ; 18(1): 25-9, 2008 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-18158242

RESUMO

The mitotic microtubule array plays two primary roles in cell division. It acts as a scaffold for the congression and separation of chromosomes, and it specifies and maintains the contractile-ring position. The current model for initiation of Drosophila and mammalian cytokinesis [1-5] postulates that equatorial localization of a RhoGEF (Pbl/Ect2) by a microtubule-associated motor protein complex creates a band of activated RhoA [6], which subsequently recruits contractile-ring components such as actin, myosin, and Anillin [1-3]. Equatorial microtubules are essential for continued constriction, but how they interact with the contractile apparatus is unknown. Here, we report the first direct molecular link between the microtubule spindle and the actomyosin contractile ring. We find that the spindle-associated component, RacGAP50C, which specifies the site of cleavage [1-5], interacts directly with Anillin, an actin and myosin binding protein found in the contractile ring [7-10]. Both proteins depend on this interaction for their localization. In the absence of Anillin, the spindle-associated RacGAP loses its association with the equatorial cortex, and cytokinesis fails. These results account for the long-observed dependence of cytokinesis on the continual presence of microtubules at the cortex.


Assuntos
Divisão Celular/fisiologia , Proteínas Contráteis/fisiologia , Proteínas de Drosophila/fisiologia , Drosophila/citologia , Proteínas Ativadoras de GTPase/fisiologia , Microtúbulos/metabolismo , Actomiosina/metabolismo , Animais , Proteínas Contráteis/análise , Proteínas Contráteis/metabolismo , Drosophila/metabolismo , Proteínas de Drosophila/análise , Proteínas de Drosophila/metabolismo , Transferência Ressonante de Energia de Fluorescência , Proteínas Ativadoras de GTPase/análise , Proteínas Ativadoras de GTPase/metabolismo , Mapeamento de Interação de Proteínas , Fuso Acromático/metabolismo
8.
IUBMB Life ; 62(4): 290-5, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20175154

RESUMO

Small GTPase pathways of the Ras superfamily are implicated in a wide range of signalling processes in animal cells. Small GTPases control pathways by acting as molecular switches. They are converted from an inactive GDP-bound form to an active GTP-bound form by GTP exchange factors (GEFs). The spatial and temporal regulation of GEFs is a major component of the regulation of small GTPases. Here we review the role of the Drosophila RhoGEF, Pebble (the Drosophila ortholog of mammalian ECT2). We discuss its roles in cytokinesis and cell migration, highlighting the diversity with which Rho family signalling pathways operate in biological systems.


Assuntos
Drosophila/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Transdução de Sinais/fisiologia , Animais
9.
Dev Cell ; 3(4): 569-79, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12408808

RESUMO

We show that the Drosophila gene rhea, isolated because its wing blister phenotype is typical of mutants affecting integrin function, encodes talin. Embryos deficient in talin have very similar phenotypes to integrin (betaPS) null embryos, including failure in germ band retraction and muscle detachment. We demonstrate that talin is not required for the presence of integrins on the cell surface or their localization at muscle termini. However, talin is required for formation of focal adhesion-like clusters of integrins on the basal surface of imaginal disc epithelia and junctional plaques between muscle and tendon cells. These results indicate that talin is essential for integrin function and acts by stably linking clusters of ECM-linked integrins to the cytoskeleton.


Assuntos
Drosophila/genética , Integrinas/genética , Talina/genética , Animais , Adesão Celular/genética , Citoesqueleto/genética , Drosophila/embriologia , Embrião não Mamífero/embriologia , Embrião não Mamífero/fisiologia , Matriz Extracelular/genética
10.
Free Radic Res ; 53(7): 705-713, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31117839

RESUMO

Genomic instability is a common feature of tumours that has a wide range of disruptive effects on cellular homeostasis. In this review we briefly discuss how instability comes about, then focus on the impact of gain or loss of DNA (aneuploidy) on oxidative stress. We discuss several mechanisms that lead from aneuploidy to the production of reactive oxygen species, including the effects on protein complex stoichiometry, endoplasmic reticulum stress and metabolic disruption. Each of these are involved in positive feedback loops that amplify relatively minor genetic changes into major cellular disruption or cell death, depending on the capacity of the cell to induce antioxidants or processes such as mitophagy that can moderate the disruption. Finally we examine the direct effects of reactive oxygen species on mitosis and how oxidative stress can compromise centrosome number, cytoskeletal integrity and signalling processes that are vital for mitotic fidelity.


Assuntos
Aneuploidia , Homeostase/fisiologia , Humanos
11.
Biol Open ; 7(10)2018 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-30327366

RESUMO

Aneuploidy -- having an unbalanced genome - is poorly tolerated at the cellular and organismal level. It gives rise to proteotoxic stress as well as a stereotypical oxidative shift which makes these cells sensitive to internal and environmental stresses. Using Drosophila as a model, we found that protein folding stress is exacerbated by redox stress that occurs in response to ongoing changes to ploidy (chromosomal instability, CIN). We also found that if de novo nucleotide synthesis is blocked, CIN cells are dependent on a high level of lysosome function to survive. Depletion of adenosine monophosphate (AMP) synthesis enzymes led to DNA damage in CIN cells, which showed elevated activity of the DNA repair enzyme activated poly(ADP ribose) polymerase (PARP). PARP activation causes depletion of its substrate, nicotinamide adenine dinucleotide (NAD+) and subsequent loss of Adenosine Tri-Phosphate (ATP), and we found that adding ATP or nicotinamide (a precursor in the synthesis of NAD+) could rescue the observed phenotypes. These findings provide ways to interpret, target and exploit aneuploidy, which has the potential to offer tumour-specific therapies.

12.
Sci Rep ; 7(1): 11531, 2017 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-28912546

RESUMO

Tumors frequently fail to pass on all their chromosomes correctly during cell division, and this chromosomal instability (CIN) causes irregular aneuploidy and oxidative stress in cancer cells. Our objective was to test knockdowns of metabolic enzymes in Drosophila to find interventions that could exploit the differences between normal and CIN cells to block CIN tumor growth without harming the host animal. We found that depleting by RNAi or feeding the host inhibitors against phosphoenolpyruvate carboxykinase (PEPCK) was able to block the growth of CIN tissue in a brat tumor explant model. Increasing NAD+ or oxidising cytoplasmic NADH was able to rescue the growth of PEPCK depleted tumors, suggesting a problem in clearing cytoplasmic NADH. Consistent with this, blocking the glycerol-3-phosphate shuttle blocked tumor growth, as well as lowering ROS levels. This work suggests that proliferating CIN cells are particularly vulnerable to inhibition of PEPCK, or its metabolic network, because of their compromised redox status.


Assuntos
Neoplasias Encefálicas/patologia , Glicólise , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Animais , Modelos Animais de Doenças , Drosophila , Células Tumorais Cultivadas
13.
Curr Drug Targets ; 17(2): 154-63, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25619750

RESUMO

The production of reactive oxygen species is a normal part of cell physiology, but many internal and external stimuli are able to trigger the production of excess levels of oxidants that are potentially damaging. The threat of oxidative damage is particularly significant to DNA, as damaged bases can interfere with replication to generate lasting mutations. Signalling through the JNK pathway is a key cellular response to oxidative damage. Depending on the intensity and duration of the damage signal, JNK signalling can lead to distinct alternative responses including DNA repair, anti-oxidant production or cell death. These responses are highly relevant to cancer therapy, as tumours are often under oxidative stress that produces elevated JNK levels and therapy often involves inducing DNA damage with the intention of driving cell death. In this review we examine the causes and consequences of JNK activation that relate to oxidative DNA damage, with a focus on the potential therapeutic implications.


Assuntos
Sistema de Sinalização das MAP Quinases , Neoplasias/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Dano ao DNA/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Estresse Oxidativo/efeitos dos fármacos
14.
Oncotarget ; 6(36): 38552-65, 2015 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-26462024

RESUMO

Chromosomal instability (CIN) is a hallmark of cancer and has been implicated in cancer initiation, progression and the development of resistance to traditional cancer therapy. Here we identify a new property of CIN cells, showing that inducing CIN in proliferating Drosophila larval tissue leads to the activation of innate immune signalling in CIN cells. Manipulation of this immune pathway strongly affects the survival of CIN cells, primarily via JNK, which responds to both Toll and TNFα/Eiger. This pathway also activates Mmp1, which recruits hemocytes to the CIN tissue to provide local amplification of the immune response that is needed for effective elimination of CIN cells.


Assuntos
Instabilidade Cromossômica/imunologia , Receptores Toll-Like/imunologia , Animais , Apoptose/genética , Apoptose/imunologia , Morte Celular/genética , Morte Celular/imunologia , Drosophila , Imunidade Inata , Estresse Oxidativo/genética , Estresse Oxidativo/imunologia , Espécies Reativas de Oxigênio/imunologia , Transdução de Sinais , Receptores Toll-Like/genética
15.
Cell Cycle ; 13(4): 622-31, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24335260

RESUMO

Chromosomal instability (CIN), as a common feature of tumors, represents a potential therapeutic target if ways can be found to specifically cause apoptosis in unstably dividing cells. We have previously shown that if signaling through the JNK pathway is reduced, apoptosis is triggered in models of chromosomal instability induced by loss of the spindle checkpoint. Here we identify components upstream and downstream of JNK that are able to mediate this effect, and test the involvement of p53 and DNA damage in causing apoptosis when JNK signaling is reduced in CIN cells. We show that cell cycle progression timing has a strong effect on the apoptosis seen when JNK signaling is reduced in genetically unstable cells: a shortened G 2 phase enhances the apoptosis, while lengthening G 2 rescues the JNK-deficient CIN cell death phenotype. Our findings suggest that chromosomal instability represents a significant stress to dividing cells, and that without JNK signaling, cells undergo apoptosis because they lack a timely and effective response to DNA damage.


Assuntos
Instabilidade Cromossômica/fisiologia , Drosophila/metabolismo , MAP Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases , Animais , Apoptose/fisiologia , Caspases/metabolismo , Dano ao DNA/fisiologia , Drosophila/genética , Proteínas de Drosophila/metabolismo , Fase G2/fisiologia , MAP Quinase Quinase 4/genética , Mitose , Proteína Supressora de Tumor p53/metabolismo
16.
PLoS One ; 7(10): e47447, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23077619

RESUMO

BACKGROUND: The spindle assembly checkpoint is crucial for the maintenance of a stable chromosome number. Defects in the checkpoint lead to Chromosomal INstability (CIN), which is linked to the progression of tumors with poor clinical outcomes such as drug resistance and metastasis. As CIN is not found in normal cells, it offers a cancer-specific target for therapy, which may be particularly valuable because CIN is common in advanced tumours that are resistant to conventional therapy. PRINCIPAL FINDINGS: Here we identify genes that are required for the viability of cells with a CIN phenotype. We have used RNAi knockdown of the spindle assembly checkpoint to induce CIN in Drosophila and then screened the set of kinase and phosphatase genes by RNAi knockdown to identify those that induce apoptosis only in the CIN cells. Genes identified include those involved in JNK signaling pathways and mitotic cytoskeletal regulation. CONCLUSIONS/SIGNIFICANCE: The screen demonstrates that it is feasible to selectively kill cells with CIN induced by spindle checkpoint defects. It has identified candidates that are currently being pursued as cancer therapy targets (e.g. Nek2: NIMA related kinase 2), confirming that the screen is able to identify promising drug targets of clinical significance. In addition, several other candidates were identified that have no previous connection with mitosis or apoptosis. Further screening and detailed characterization of the candidates could potentially lead to the therapies that specifically target advanced cancers that exhibit CIN.


Assuntos
Apoptose , Proteínas de Ciclo Celular , Instabilidade Cromossômica/genética , Pontos de Checagem da Fase M do Ciclo Celular/genética , Proteínas Serina-Treonina Quinases , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/isolamento & purificação , Proteínas de Ciclo Celular/metabolismo , Sobrevivência Celular/genética , Citoesqueleto/metabolismo , Drosophila/genética , Drosophila/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases , Terapia de Alvo Molecular , Quinase 1 Relacionada a NIMA , Monoéster Fosfórico Hidrolases/genética , Monoéster Fosfórico Hidrolases/metabolismo , Fosfotransferases/genética , Fosfotransferases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/isolamento & purificação , Proteínas Serina-Treonina Quinases/metabolismo
17.
Commun Integr Biol ; 4(2): 243-4, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21655452

RESUMO

Appropriate assembly and constriction of the acto-myosin based contractile ring is essential for the final separation of the two daughter cells in mitosis. This is orchestrated by the small GTPase Rho as well as convergent signals from the prior events of mitosis. Contractile ring assembly requires the physical interaction of structural proteins like the microtubules of the central spindle, motor proteins and Rho activators. These and the interaction of newly localised proteins downstream of active Rho are essential for stability of the contractile ring and its proper constriction. Here, we discuss our recent findings that reveal a complex network of protein interactions during the early stages of cytokinesis. This includes evidence for a direct interaction between Polo Kinase and RacGAP50C as well as unpublished data suggesting other interactions of interest within the contractile ring.

18.
Fly (Austin) ; 1(1): 13-22, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18690061

RESUMO

To identify genes that modulate Rho signalling during cytokinesis we tested the effect of overexpressing a set of 2190 genes on an eye phenotype caused by defective Rho activation. The resulting 112 modifier loci fell into three main classes: cell cycle genes, signalling effectors and metabolic enzymes. We developed a further series of genetic tests to refine the interactors into those most likely to modify Rho signalling during cytokinesis. In addition to a number of genes previously implicated in the Rho pathway during cytokinesis, we identified four novel primary candidates: cdc14, Pitslre, PDK1 and thread/diap1. cdc14 orthologs have, however, been implicated in cytokinesis in other organisms, as have molecules related to Thread/Diap1. The identification of several modifiers that are genetically redundant paralogs highlights the ability of overexpression screens to identify genes that are refractory to traditional loss-of-function approaches. Overexpression screens and sensitized phenotypes, therefore, may help identify the many factors that are expected to be involved in cytokinesis but have not been discovered by previous genetic screens.


Assuntos
Citocinese , Proteínas de Drosophila/metabolismo , Drosophila/genética , Marcadores Genéticos , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Drosophila/metabolismo , Olho/anatomia & histologia , Interferência de RNA , Transdução de Sinais , Asas de Animais/anatomia & histologia
19.
J Cell Sci ; 115(Pt 22): 4215-25, 2002 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-12376554

RESUMO

Recent studies have characterised a family of giant cytoskeletal crosslinkers encoded by the short stop gene in Drosophila and the dystonin/BPAG1 and MACF1 genes in mammals. We refer to the products of these genes as spectraplakins to highlight the fact that they share features with both the spectrin and plakin superfamilies. These genes produce a variety of large proteins, up to almost 9000 residues long, which can potentially extend 0.4 micro m across a cell. Spectraplakins can interact with all three elements of the cytoskeleton: actin, microtubules and intermediate filaments. The analysis of mutant phenotypes in BPAG1 in mouse and short stop in Drosophila demonstrates that spectraplakins have diverse roles. These include linking the plasma membrane and the cytoskeleton, linking together different elements of the cytoskeleton and organising membrane domains.


Assuntos
Autoantígenos/metabolismo , Proteínas de Transporte , Colágeno/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas de Drosophila/metabolismo , Células Eucarióticas/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso , Colágenos não Fibrilares , Espectrina/metabolismo , Actinas/metabolismo , Animais , Autoantígenos/genética , Membrana Celular/metabolismo , Membrana Celular/ultraestrutura , Colágeno/genética , Proteínas do Citoesqueleto/genética , Proteínas de Drosophila/genética , Distonina , Células Eucarióticas/ultraestrutura , Humanos , Filamentos Intermediários/genética , Filamentos Intermediários/metabolismo , Proteínas dos Microfilamentos/genética , Microtúbulos/metabolismo , Espectrina/genética , Colágeno Tipo XVII
20.
Development ; 131(20): 5053-63, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15459099

RESUMO

Pebble (Pbl)-activated RhoA signalling is essential for cytokinesis in Drosophila melanogaster. Here we report that the Drosophila citron gene encodes an essential effector kinase of Pbl-RhoA signalling in vivo. Drosophila citron is expressed in proliferating tissues but is downregulated in differentiating tissues. We find that Citron can bind RhoA and that localisation of Citron to the contractile ring is dependent on the cytokinesis-specific Pbl-RhoA signalling. Phenotypic analysis of mutants showed that citron is required for cytokinesis in every tissue examined, with mutant cells exhibiting multinucleate and hyperploid phenotypes. Strong genetic interactions were observed between citron and pbl alleles and constructs. Vertebrate studies implicate at least two Rho effector kinases, Citron and Rok, in cytokinesis. By contrast, we failed to find evidence for a role for the Drosophila ortholog of Rok in cell division. We conclude that Citron plays an essential, non-redundant role in the Rho signalling pathway during Drosophila cytokinesis.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Diferenciação Celular , Divisão Celular/fisiologia , Sequência Conservada , Drosophila melanogaster/enzimologia , Evolução Molecular , Peptídeos e Proteínas de Sinalização Intracelular , Mutação , Poliploidia , Proteínas Serina-Treonina Quinases/genética , Análise de Sequência de Proteína , Transdução de Sinais/fisiologia
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