RESUMO
The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole-exome sequencing, methylated DNA immunoprecipitation sequencing, and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter that is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity toward venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter's syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.
Assuntos
Neoplasias Hematológicas , Leucemia Linfocítica Crônica de Células B , Linfoma Difuso de Grandes Células B , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas Reguladoras de Apoptose/genética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Linfoma Difuso de Grandes Células B/patologia , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Epigênese GenéticaRESUMO
Examination of the tumour suppressor adenomatous polyposis coli (APC) has shown that it may be multifunctional. Recent work has demonstrated dynamic interactions of APC with the microtubule cytoskeleton, supporting the idea that APC has an important function in cell migration.
Assuntos
Proteínas do Citoesqueleto/fisiologia , Genes Supressores de Tumor/fisiologia , Microtúbulos/fisiologia , Proteína da Polipose Adenomatosa do Colo , Movimento Celular/fisiologia , Proteínas de Neoplasias/fisiologiaRESUMO
Proper positioning of mitotic spindles ensures equal allocation of chromosomes to daughter cells. This often involves interactions between spindle and astral microtubules and cortical actin. In yeast and Caenorhabditis elegans, some of the protein machinery that connects spindles and cortex has been identified but, in most animal cells, this process remains mysterious. Here, we report that the tumour suppressor homologue APC2 and its binding partner Armadillo both play roles in spindle anchoring during the syncytial mitoses of early Drosophila embryos. Armadillo, alpha-catenin and APC2 all localize to sites of cortical spindle attachment. APC2-Armadillo complexes often localize with interphase microtubules. Zeste-white 3 kinase, which can phosphorylate Armadillo and APC, is also crucial for spindle positioning and regulates the localization of APC2-Armadillo complexes. Together, these data suggest that APC2, Armadillo and alpha-catenin provide an important link between spindles and cortical actin, and that this link is regulated by Zeste-white 3 kinase.
Assuntos
Actinas/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas de Drosophila , Drosophila melanogaster/embriologia , Quinase 3 da Glicogênio Sintase , Proteínas de Insetos/metabolismo , Fuso Acromático/metabolismo , Transativadores , Animais , Proteínas do Domínio Armadillo , Caderinas/metabolismo , Proteínas do Citoesqueleto/genética , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Células Gigantes/metabolismo , Humanos , Microscopia de Fluorescência , Mitose , Proteínas Serina-Treonina Quinases/metabolismo , Fuso Acromático/ultraestrutura , Fatores de Transcrição , alfa CateninaRESUMO
The distribution of guanine and cytosine nucleotides throughout a genome, or the GC content, is associated with numerous features in mammals; understanding the pattern and evolutionary history of GC content is crucial to our efforts to annotate the genome. The local GC content is decaying toward an equilibrium point, but the causes and rates of this decay, as well as the value of the equilibrium point, remain topics of debate. By comparing the results of 2 methods for estimating local substitution rates, we identify 620 Mb of the human genome in which the rates of the various types of nucleotide substitutions are the same on both strands. These strand-symmetric regions show an exponential decay of local GC content at a pace determined by local substitution rates. DNA segments subjected to higher rates experience disproportionately accelerated decay and are AT rich, whereas segments subjected to lower rates decay more slowly and are GC rich. Although we are unable to draw any conclusions about causal factors, the results support the hypothesis proposed by Khelifi A, Meunier J, Duret L, and Mouchiroud D (2006. GC content evolution of the human and mouse genomes: insights from the study of processed pseudogenes in regions of different recombination rates. J Mol Evol. 62:745-752.) that the isochore structure has been reshaped over time. If rate variation were a determining factor, then the current isochore structure of mammalian genomes could result from the local differences in substitution rates. We predict that under current conditions strand-symmetric portions of the human genome will stabilize at an average GC content of 30% (considerably less than the current 42%), thus confirming that the human genome has not yet reached equilibrium.
Assuntos
Composição de Bases/genética , Evolução Molecular , Genoma Humano , Isocoros/genética , Humanos , Mutação/genéticaRESUMO
MOTIVATION: In this article we build a model of the CpG dinucleotide substitution rate and use it to challenge the claim that, that rate underwent a sudden mammalian-specific increase approximately 90 million years ago. The evidence supporting this hypothesis comes from the application of a model of neutral substitution rates able to account for elevated CpG dinucleotide substitution rates. With the initial goal of improving that model's accuracy, we introduced a modification enabling us to account for boundary effects arising by the truncation of the Markov field, as well as improving the optimization procedure required for estimating the substitution rates. RESULTS: When using this modified method to reproduce the supporting analysis, the evidence of the rate shift vanished. Our analysis suggests that the CpG-specific rate has been constant over the relevant time period and that the asserted acceleration of the CpG rate is likely an artifact of the original model.
Assuntos
Ilhas de CpG , Evolução Molecular , Algoritmos , Animais , Metilação de DNA , Genoma , Genoma Humano , Humanos , Mamíferos , Cadeias de Markov , CamundongosRESUMO
The products of the Drosophila segment polarity gene armadillo and its vertebrate homologue beta-catenin are components of the signal transduction pathway for Wingless/Wnt-1; this signal regulates cell-fate choices in embryos of the fruit fly Drosophila and vertebrates. Armadillo/beta-catenin is also a component of cell-cell adherens junctions in epithelia. How can these two seemingly distinct roles be reconciled? Evidence suggests that Armadillo has distinct functions: one in the adherens junction and one or more in the cytoplasm. The biochemical role of Armadillo may be to serve as a scaffold upon which different multiprotein complexes are assembled.
RESUMO
Armadillo, the Drosophila homologue of vertebrate beta-catenin, plays a pivotal role both in Wingless signaling and in assembly of adherens junctions. We performed the first in vivo structure-function study of an adherens junction protein, by generating and examining a series of Armadillo mutants in the context of the entire animal. We tested each mutant by assaying its biological function, its ability to bind proteins that normally associate with Armadillo in adherens junctions, its cellular localization, and its pattern of phosphorylation. We mapped the binding sites for DE-cadherin and alpha-catenin. Although these bind to Armadillo independently of each other, binding of each is required for the function of adherens junctions. We identified two separate regions of Armadillo critical for Wingless signaling. We demonstrated that endogenous Armadillo accumulates in the nucleus and provide evidence that it may act there in transducing Wingless signal. We found that the Arm repeats, which make up the central two-thirds of Armadillo, differ among themselves in their functional importance in different processes. Finally, we demonstrated that Armadillo's roles in adherens junctions and Wingless signaling are independent. We discuss the potential biochemical role of Armadillo in each process.
Assuntos
Adesão Celular , Proteínas de Drosophila , Proteínas/fisiologia , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais/fisiologia , Transativadores , Alelos , Animais , Proteínas do Domínio Armadillo , Sequência de Bases , Caderinas/metabolismo , Núcleo Celular/metabolismo , Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/metabolismo , Proteínas do Citoesqueleto/fisiologia , DNA , Drosophila/genética , Drosophila/metabolismo , Feminino , Teste de Complementação Genética , Humanos , Hormônios de Inseto/química , Hormônios de Inseto/fisiologia , Masculino , Dados de Sequência Molecular , Mutagênese , Fosforilação , Proteínas/química , Proteínas/genética , Relação Estrutura-Atividade , Fatores de Transcrição , Proteína Wnt1 , alfa Catenina , beta CateninaRESUMO
Morphological and biochemical analyses have identified a set of proteins which together form a structure known as the adherens junction. Elegant experiments in tissue culture support the idea that adherens junctions play a key role in cell-cell adhesion and in organizing cells into epithelia. During normal embryonic development, cells quickly organize epithelia; these epithelial cells participate in many of the key morphogenetic movements of gastrulation. This prompted the hypothesis that adherens junctions ought to be critical for normal embryonic development. Drosophila Armadillo, the homologue of vertebrate beta-catenin, is a core component of the adherens junction protein complex and has been hypothesized to be essential for adherens junction function in vivo. We have used an intermediate mutant allele of armadillo, armadilloXP33, to test these hypotheses in Drosophila embryos. Adherens junctions cannot assemble in the absence of Armadillo, leading to dramatic defects in cell-cell adhesion. The epithelial cells of the embryo lose adhesion to each other, round up, and apparently become mesenchymal. Mutant cells also lose their normal cell polarity. These disruptions in the integrity of epithelia block the appropriate morphogenetic movements of gastrulation. These results provide the first demonstration of the effect of loss of adherens junctions on Drosophila embryonic development.
Assuntos
Moléculas de Adesão Celular/fisiologia , Adesão Celular , Polaridade Celular , Proteínas de Drosophila , Drosophila melanogaster/embriologia , Morfogênese , Proteínas/fisiologia , Transativadores , Citoesqueleto de Actina/ultraestrutura , Actinas/metabolismo , Animais , Proteínas do Domínio Armadillo , Caderinas/metabolismo , Proteínas do Citoesqueleto/metabolismo , Análise Mutacional de DNA , Células Epiteliais , Gástrula/citologia , Junções Intercelulares/ultraestrutura , Proteínas de Membrana/fisiologia , Microscopia Eletrônica de Varredura , Oogênese , Fatores de Transcrição , alfa CateninaRESUMO
Activation of the nonreceptor tyrosine kinase Abelson (Abl) contributes to the development of leukemia, but the complex roles of Abl in normal development are not fully understood. Drosophila Abl links neural axon guidance receptors to the cytoskeleton. Here we report a novel role for Drosophila Abl in epithelial cells, where it is critical for morphogenesis. Embryos completely lacking both maternal and zygotic Abl die with defects in several morphogenetic processes requiring cell shape changes and cell migration. We describe the cellular defects that underlie these problems, focusing on dorsal closure as an example. Further, we show that the Abl target Enabled (Ena), a modulator of actin dynamics, is involved with Abl in morphogenesis. We find that Ena localizes to adherens junctions of most epithelial cells, and that it genetically interacts with the adherens junction protein Armadillo (Arm) during morphogenesis. The defects of abl mutants are strongly enhanced by heterozygosity for shotgun, which encodes DE-cadherin. Finally, loss of Abl reduces Arm and alpha-catenin accumulation in adherens junctions, while having little or no effect on other components of the cytoskeleton or cell polarity machinery. We discuss possible models for Abl function during epithelial morphogenesis in light of these data.
Assuntos
Axônios/fisiologia , Drosophila/genética , Proteínas Ativadoras de GTPase/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Fenômenos Fisiológicos do Sistema Nervoso , Receptores Imunológicos/metabolismo , Células 3T3 , Actinas/metabolismo , Animais , Axônios/ultraestrutura , Drosophila/fisiologia , Fibroblastos/citologia , Fibroblastos/fisiologia , Biblioteca Gênica , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Fenótipo , Fatores de Troca de Nucleotídeo Guanina Rho , Transdução de Sinais , Proteínas RoundaboutRESUMO
Three proteins identified by quite different criteria in three different systems, the Drosophila segment polarity gene armadillo, the human desmosomal protein plakoglobin, and the Xenopus E-cadherin-associated protein beta-catenin, share amino acid sequence similarity. These findings raise questions about the relationship among the three molecules and their roles in different cell-cell adhesive junctions. We have found that antibodies against the Drosophila segment polarity gene armadillo cross react with a conserved vertebrate protein. This protein is membrane associated, probably via its interaction with a cadherin-like molecule. This cross-reacting protein is the cadherin-associated protein beta-catenin. Using anti-armadillo and antiplakoglobin antibodies, it was shown that beta-catenin and plakoglobin are distinct molecules, which can coexist in the same cell type. Plakoglobin interacts with the desmosomal glycoprotein desmoglein I, and weakly with E-cadherin. Although beta-catenin interacts tightly with E-cadherin, it does not seem to be associated with either desmoglein I or with isolated desmosomes. Anti-armadillo antibodies have been further used to determine the intracellular localization of beta-catenin, and to examine its tissue distribution. The implications of these results for the structure and function of different cell-cell adhesive junctions are discussed.
Assuntos
Caderinas/genética , Moléculas de Adesão Celular/genética , Proteínas do Citoesqueleto/genética , Proteínas de Drosophila , Drosophila/genética , Família Multigênica , Proteínas/genética , Transativadores , Sequência de Aminoácidos , Animais , Proteínas do Domínio Armadillo , Caderinas/metabolismo , Moléculas de Adesão Celular/imunologia , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Reações Cruzadas , Proteínas do Citoesqueleto/imunologia , Proteínas do Citoesqueleto/metabolismo , Desmogleína 1 , Desmogleínas , Desmoplaquinas , Eletroforese em Gel de Poliacrilamida , Imunofluorescência , Humanos , Junções Intercelulares/metabolismo , Camundongos , Dados de Sequência Molecular , Proteínas/imunologia , Proteínas/metabolismo , Homologia de Sequência do Ácido Nucleico , Fatores de Transcrição , beta Catenina , gama CateninaRESUMO
The tumor suppressor adenomatous polyposis coli (APC) negatively regulates Wingless (Wg)/Wnt signal transduction by helping target the Wnt effector beta-catenin or its Drosophila homologue Armadillo (Arm) for destruction. In cultured mammalian cells, APC localizes to the cell cortex near the ends of microtubules. Drosophila APC (dAPC) negatively regulates Arm signaling, but only in a limited set of tissues. We describe a second fly APC, dAPC2, which binds Arm and is expressed in a broad spectrum of tissues. dAPC2's subcellular localization revealed colocalization with actin in many but not all cellular contexts, and also suggested a possible interaction with astral microtubules. For example, dAPC2 has a striking asymmetric distribution in neuroblasts, and dAPC2 colocalizes with assembling actin filaments at the base of developing larval denticles. We identified a dAPC2 mutation, revealing that dAPC2 is a negative regulator of Wg signaling in the embryonic epidermis. This allele acts genetically downstream of wg, and upstream of arm, dTCF, and, surprisingly, dishevelled. We discuss the implications of our results for Wg signaling, and suggest a role for dAPC2 as a mediator of Wg effects on the cytoskeleton. We also speculate on more general roles that APCs may play in cytoskeletal dynamics.
Assuntos
Proteínas do Citoesqueleto/metabolismo , Citoesqueleto/metabolismo , Proteínas de Drosophila , Drosophila melanogaster/metabolismo , Epiderme/embriologia , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais , Transativadores , Actinas/metabolismo , Sequência de Aminoácidos , Animais , Proteínas do Domínio Armadillo , Clonagem Molecular , Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/genética , Drosophila melanogaster/citologia , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Células Epidérmicas , Epiderme/metabolismo , Epistasia Genética , Feminino , Genes de Insetos/genética , Genes de Insetos/fisiologia , Humanos , Proteínas de Insetos/química , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Larva/citologia , Masculino , Dados de Sequência Molecular , Mutação/genética , Neurônios/citologia , Neurônios/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas/genética , Fuso Acromático/metabolismo , Fatores de Transcrição , Células Tumorais Cultivadas , Proteína Wnt1RESUMO
The classical adherens junction that holds epithelial cells together consists of a protein complex in which members of the cadherin family linked to various catenins are the principal components. delta-catenin is a mammalian brain protein in the Armadillo repeat superfamily with sequence similarity to the adherens junction protein p120(ctn). We found that delta-catenin can be immunoprecipitated as a complex with other components of the adherens junction, including cadherin and beta-catenin, from transfected cells and brain. The interaction with cadherin involves direct contact within the highly conserved juxtamembrane region of the COOH terminus, where p120(ctn) also binds. In developing mouse brain, staining with delta-catenin antibodies is prominent towards the apical boundary of the neuroepithelial cells in the ventricular zone. When transfected into Madin-Darby canine kidney (MDCK) epithelial cells delta-catenin colocalized with cadherin, p120(ctn), and beta-catenin. The Arm domain alone was sufficient for achieving localization and coimmunoprecipitation with cadherin. The ectopic expression of delta-catenin in MDCK cells altered their morphology, induced the elaboration of lamellipodia, interfered with monolayer formation, and increased scattering in response to hepatocyte growth factor treatment. We propose that delta-catenin can regulate adhesion molecules to implement the organization of large cellular arrays necessary for tissue morphogenesis.
Assuntos
Movimento Celular/fisiologia , Proteínas de Drosophila , Proteínas do Tecido Nervoso/fisiologia , Transativadores , Animais , Proteínas do Domínio Armadillo , Sequência de Bases , Sítios de Ligação/genética , Encéfalo/metabolismo , Caderinas/genética , Caderinas/isolamento & purificação , Caderinas/fisiologia , Cateninas , Adesão Celular/fisiologia , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/fisiologia , Linhagem Celular , Tamanho Celular/fisiologia , Proteínas do Citoesqueleto/química , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/isolamento & purificação , Proteínas do Citoesqueleto/fisiologia , Primers do DNA/genética , Cães , Humanos , Proteínas de Insetos/química , Proteínas de Insetos/genética , Camundongos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Fosfoproteínas , Transfecção , beta Catenina , delta CateninaRESUMO
All animal cells have a polarity, that is, different proteins are clustered in distinct domains of the plasma membrane and these regions carry out different jobs. As Peifer discusses in a lively Perspective, new work (Bilder et al.) identifies some of the molecular characters that direct proteins to their different cellular destinations.
Assuntos
Divisão Celular , Polaridade Celular , Proteínas de Drosophila , Proteínas de Membrana/metabolismo , Neoplasias/etiologia , Proteínas Supressoras de Tumor , Animais , Transporte Biológico , Membrana Celular/metabolismo , Transformação Celular Neoplásica , Citoplasma/metabolismo , Drosophila/citologia , Drosophila/genética , Drosophila/metabolismo , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Genes Supressores de Tumor , Proteínas de Insetos/química , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Junções Intercelulares/metabolismo , Proteínas de Membrana/química , Mutação , Neoplasias/metabolismo , Fenótipo , Estrutura Terciária de ProteínaRESUMO
Recombinant DNA clones containing large pieces of DNA are useful in the study of large genetic units, but these are difficult to make in most bacterial cloning vectors. A strategy is described that uses general and site-specific recombination to construct large pieces of eukaryotic DNA from smaller cloned segments. The large clones are propagated on F factor-based plasmids in Escherichia coli. They can be easily modified to introduce mutations or rearrangements. These techniques were applied to the construction of large DNA segments from the bithorax complex of Drosophila.
Assuntos
DNA Recombinante/biossíntese , Escherichia coli/genética , Fator F , Transformação Bacteriana , DNA Super-Helicoidal/biossíntese , Vetores Genéticos , Mutação , PlasmídeosRESUMO
The bithorax complex in Drosophila melanogaster is a cluster of homeotic genes that specify developmental pathways for many of the body segments of the fly. The DNA of the bithorax complex has been isolated, and a region of 195,000 base pairs that covers the left half of the complex is described here. The lesions associated with many of the bithorax complex mutants have been identified, and most are due to DNA rearrangements. Most of the spontaneous mutants have insertions of a particular mobile element named "gypsy." This element affects the functions of sequences removed from the site of insertion. Mutant lesions for a given phenotypic class are distributed over large DNA distances of up to 73,000 base pairs.
RESUMO
Proper cell-cell adhesion and communication are essential for normal development and are often perturbed during tumor formation. We have come to realize that cell-cell junctions not only mediate intercellular adhesion, but also serve as organizing centers for specific cell-cell signaling pathways. The characterization of protein components of adhesive and tight/septate junctions in vertebrates and Drosophila is reviewed, and their roles in adhesion and signaling discussed. Many molecules that mediate intercellular signaling, including certain tumor suppressor gene products, are localized to particular cell-cell junctions, suggesting that disruption of junctional signaling pathways contributes to tumorigenesis.
Assuntos
Adesão Celular , Junções Intercelulares , Transdução de Sinais , Animais , Comunicação Celular , HumanosRESUMO
Within the past year, Armadillo and beta-catenin's role in transducing the Wingless/Wnt signal has been substantially clarified. It is now clear that Armadillo and beta-catenin bind directly to members of the T-cell factor/lymphoid enhancer factor subfamily of HMG box DNA-binding proteins, forming bipartite transcription factors that regulate Wingless/Wnt responsive genes in both Drosophila and vertebrates. These partners not only play key roles in a variety of cell fate decisions during normal development but, when inappropriately activated, contribute to both colon cancer and melanoma.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas de Drosophila , Proteínas de Insetos/metabolismo , Transativadores , Fatores de Transcrição/metabolismo , Animais , Proteínas do Domínio Armadillo , Adesão Celular , Movimento Celular , Proteínas do Citoesqueleto/metabolismo , Drosophila/genética , Drosophila/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Fator 1 de Ligação ao Facilitador Linfoide , Ligação Proteica , Transdução de Sinais , beta CateninaRESUMO
T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Dano ao DNA , Epigênese Genética , Leucemia Prolinfocítica de Células T/genética , Proteínas Proto-Oncogênicas/genética , Adulto , Idoso , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica/métodos , Células HEK293 , Humanos , Estimativa de Kaplan-Meier , Leucemia Prolinfocítica de Células T/tratamento farmacológico , Leucemia Prolinfocítica de Células T/metabolismo , Masculino , Camundongos Transgênicos , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas/metabolismoRESUMO
A novel class of receptor-the Frizzled family-has been identified and the members shown to be receptors for Wingless and its homologs, the Wnts, which mediate key cell-cell interactions during the development of fruitflies and vertebrates, respectively.
Assuntos
Proteínas de Drosophila , Drosophila/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores de Neurotransmissores , Transdução de Sinais/fisiologia , Animais , Comunicação Celular , Receptores Frizzled , Proteínas Hedgehog , Humanos , Proteínas de Insetos/metabolismo , Receptores Acoplados a Proteínas G , Proteína Wnt1RESUMO
BACKGROUND: Neural development requires that neurons communicate and co-operate with one another and with other cell types in their environment. Drosophila Armadillo and its vertebrate homolog beta-catenin have dual roles in epithelial cells: transducing signals from the Wingless/Wnt family of proteins and working with cadherins to mediate cell adhesion. Wingless/Wnt signaling also directs certain cell fates in the central nervous system (CNS), and cadherins and catenins are thought to function together during neural development. RESULTS: We identified and analyzed the biochemical properties of a second armadillo isoform, with a truncated carboxyl terminus generated by alternative splicing. This isoform was found to accumulate in differentiating neurons. Using armadillo alleles that selectively inactivate the cell adhesion or the Wingless signaling functions of Armadillo, we found that Armadillo had two sequential roles in neural development. Armadillo function in Wingless signal transduction was required early in development for determination of neuroblast fate. Later in development, disruption of the cell-cell adhesion function of Armadillo resulted in subtle defects in the construction of the axonal scaffold. Mutations in the gene encoding the Drosophila tyrosine kinase Abelson substantially enhanced the severity of the CNS phenotype of armadillo mutations, consistent with these proteins functioning co-operatively at adherens junctions in both the CNS and the epidermis. CONCLUSIONS: This is one of the first demonstrations of a role for the cadherin-catenin system in the normal development of the CNS. The genetic interactions between armadillo and abelson point to a possible role for the tyrosine kinase Abelson in cell-cell adhesive junctions in both the CNS and the epidermis.