RESUMO
While rare pathogenic copy-number variants (CNVs) are associated with both neuronal and non-neuronal phenotypes, functional studies evaluating these regions have focused on the molecular basis of neuronal defects. We report a systematic functional analysis of non-neuronal defects for homologs of 59 genes within ten pathogenic CNVs and 20 neurodevelopmental genes in Drosophila melanogaster. Using wing-specific knockdown of 136 RNA interference lines, we identified qualitative and quantitative phenotypes in 72/79 homologs, including 21 lines with severe wing defects and six lines with lethality. In fact, we found that 10/31 homologs of CNV genes also showed complete or partial lethality at larval or pupal stages with ubiquitous knockdown. Comparisons between eye and wing-specific knockdown of 37/45 homologs showed both neuronal and non-neuronal defects, but with no correlation in the severity of defects. We further observed disruptions in cell proliferation and apoptosis in larval wing discs for 23/27 homologs, and altered Wnt, Hedgehog and Notch signaling for 9/14 homologs, including AATF/Aatf, PPP4C/Pp4-19C, and KIF11/Klp61F. These findings were further supported by tissue-specific differences in expression patterns of human CNV genes, as well as connectivity of CNV genes to signaling pathway genes in brain, heart and kidney-specific networks. Our findings suggest that multiple genes within each CNV differentially affect both global and tissue-specific developmental processes within conserved pathways, and that their roles are not restricted to neuronal functions.
Assuntos
Variações do Número de Cópias de DNA , Proteínas de Drosophila/genética , Regulação da Expressão Gênica no Desenvolvimento , Transtornos do Neurodesenvolvimento/genética , Animais , Olho Composto de Artrópodes/embriologia , Olho Composto de Artrópodes/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Especificidade de Órgãos , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais , Asas de Animais/embriologia , Asas de Animais/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismoRESUMO
The Hippo tumor suppressor pathway plays an important role in tissue homeostasis that ensures development of functional organs at proper size. The YAP transcription coactivator is a major effector of the Hippo pathway and is phosphorylated and inactivated by the Hippo pathway kinases Lats1/2. It has recently been shown that YAP activity is regulated by G-protein-coupled receptor signaling. Here we demonstrate that cyclic adenosine monophosphate (cAMP), a second messenger downstream from Gαs-coupled receptors, acts through protein kinase A (PKA) and Rho GTPases to stimulate Lats kinases and YAP phosphorylation. We also show that inactivation of YAP is crucial for PKA-induced adipogenesis. In addition, PKA activation in Drosophila inhibits the expression of Yorki (Yki, a YAP ortholog) target genes involved in cell proliferation and death. Taken together, our study demonstrates that Hippo-YAP is a key signaling branch of cAMP and PKA and reveals new insight into mechanisms of PKA in regulating a broad range of cellular functions.
Assuntos
Diferenciação Celular , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas de Drosophila/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Aciltransferases , Adipogenia , Animais , Linhagem Celular , Proliferação de Células , AMP Cíclico/metabolismo , Proteínas de Drosophila/antagonistas & inibidores , Drosophila melanogaster/enzimologia , Drosophila melanogaster/metabolismo , Ativação Enzimática , Humanos , Camundongos , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Fosforilação , Sistemas do Segundo Mensageiro/fisiologia , Serina-Treonina Quinase 3 , Transativadores/antagonistas & inibidores , Transativadores/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas de Sinalização YAP , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
How organ growth is regulated in multicellular organisms is a long-standing question in developmental biology. It is known that coordination of cell apoptosis and proliferation is critical in cell number and overall organ size control, while how these processes are regulated is still under investigation. In this study, we found that functional loss of a gene in Drosophila, named Drosophila defender against apoptotic cell death 1 (dDad1), leads to a reduction of tissue growth due to increased apoptosis and lack of cell proliferation. The dDad1 protein, an orthologue of mammalian Dad1, was found to be crucial for protein N-glycosylation in developing tissues. Our study demonstrated that loss of dDad1 function activates JNK signaling and blocking the JNK pathway in dDad1 knock-down tissues suppresses cell apoptosis and partially restores organ size. In addition, reduction of dDad1 triggers ER stress and activates unfolded protein response (UPR) signaling, prior to the activation of JNK signaling. Furthermore, Perk-Atf4 signaling, one branch of UPR pathways, appears to play a dual role in inducing cell apoptosis and mediating compensatory cell proliferation in this dDad1 knock-down model.
Assuntos
Proteínas de Drosophila/genética , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/genética , Genes de Insetos , Morfogênese/genética , Animais , Apoptose/genética , Biocatálise , Proliferação de Células , Células Clonais , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/metabolismo , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Técnicas de Silenciamento de Genes , Glicosilação , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Sistema de Sinalização das MAP Quinases , Modelos Biológicos , Mutação/genética , Subunidades Proteicas/metabolismo , Frações Subcelulares/metabolismoRESUMO
Hippo (Hpo) signaling plays a critical role in restricting tissue growth and organ size in both invertebrate and vertebrate animals. However, how the Hpo kinase is regulated during development has not been clearly understood. Using a Bimolecular Fluorescence Complementation assay, we have investigated the functional significance of Hpo homo-dimer formation and subcellular localization in living cells. We found that Hpo dimerization and membrane association are critical for its activation in growth inhibition. As dimerization facilitates Hpo to access its binding partner, Hpo kinases in the homo-dimer trans-phosphorylate each other to increase their enzymatic activity. Moreover, loss- and gain-of-function studies indicate that upstream regulators, Expanded, Merlin and Kibra, play a critical role in promoting Hpo dimerization as well as association to the cortical F-actin beneath the plasma membrane. Enforced Hpo localization to the plasma membrane increases Hpo dimerization and activity. Therefore, homo-dimerization and plasma membrane association are two important mechanisms for Hpo activation in growth control during animal development.
Assuntos
Membrana Celular/enzimologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/enzimologia , Drosophila melanogaster/crescimento & desenvolvimento , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Multimerização Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Sobrevivência Celular , Drosophila melanogaster/anatomia & histologia , Ativação Enzimática , Fluorescência , Genes Dominantes , Mutação , Tamanho do Órgão , Fosforilação , Ligação Proteica , Transporte Proteico , Frações Subcelulares/enzimologiaRESUMO
BRMS1 was first discovered as a human breast carcinoma metastasis suppressor gene. However, the mechanism of BRMS1 in tumor metastasis and its developmental role remain unclear. In this paper, we first report the identification of the Drosophila ortholog of human BRMS1, dBrms1. Through a genetic approach, the role of dBrms1 during development has been investigated. We found that dBrms1 is an essential gene and loss of dBrms1 function results in lethality at early developmental stages. dBrms1mutants displayed phenotypes such as developmental delay and failure to initiate metamorphosis. Further analysis suggests that these phenotypes are contributed by defective ecdysone signaling and expression of target genes of the ecdysone pathway. Therefore, dBrms1 is required for growth control by acting as a modulator of ecdysone signaling in Drosophila and is required for metamorphosis for normal development.
Assuntos
Ecdisona/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Genes Supressores de Tumor , Proteínas de Neoplasias/genética , Animais , Drosophila , Metamorfose Biológica , Mutação , Proteínas Repressoras , Transdução de Sinais , Fatores de Tempo , TransgenesRESUMO
Tissue growth is achieved through coordinated cellular growth, cell division and apoptosis. Hippo signaling is critical for monitoring tissue growth during animal development. Loss of Hippo signaling leads to tissue overgrowth due to continuous cell proliferation and block of apoptosis. As cells lacking Hippo signaling are similar in size compared to normal cells, cellular growth must be properly maintained in Hippo signaling-deficient cells. However, it is not clear how Hippo signaling might regulate cellular growth. Here we show that loss of Hippo signaling increased Akt (also called Protein Kinase B, PKB) expression and activity, whereas activation of Hippo signaling reduced Akt expression in developing tissues in Drosophila. While yorkie (yki) is sufficient to increase Akt expression, Akt up-regulation caused by the loss of Hippo signaling is strongly dependent on yki, indicating that Hippo signaling negatively regulates Akt expression through Yki inhibition. Consistently, genetic analysis revealed that Akt plays a critical role in facilitating growth of Hippo signaling-defective tissues. Thus, Hippo signaling not only blocks cell division and promotes apoptosis, but also regulates cellular growth by inhibiting the Akt pathway activity.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/enzimologia , Drosophila melanogaster/crescimento & desenvolvimento , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Animais , Tamanho Celular , Regulação para Baixo/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Regulação da Expressão Gênica no Desenvolvimento , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Tamanho do Órgão/genética , Fenótipo , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/genética , Transativadores/genética , Transativadores/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Asas de Animais/anatomia & histologia , Asas de Animais/citologia , Proteínas de Sinalização YAPRESUMO
The evolutionarily conserved Hippo signaling pathway plays an important role in regulating normal development as well as tumorigenesis in animals. How this growth-inhibitory signaling is maintained at an appropriate level through feedback mechanisms is less understood. In this report, we show that bantam microRNA functions to increase the level of the Mob as tumor suppressor protein Mats, a core component of the Hippo pathway, but does not regulate mats at the transcript level. Genetic analysis also supports that bantam plays a positive role in regulating mats function for tissue growth control. Our data support a model that bantam up-regulates Mats expression through an unidentified factor that may control Mats stability.
Assuntos
Proteínas de Drosophila/genética , Drosophila/metabolismo , MicroRNAs/genética , Proteínas Supressoras de Tumor/genética , Animais , Drosophila/crescimento & desenvolvimento , Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , MicroRNAs/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Regulação para CimaRESUMO
Growth inhibition mediated by Hippo (Hpo) signaling is essential for tissue growth and organ size control in Drosophila. However, the cellular mechanism by which the core components like Mob as tumor suppressor (Mats) and Warts (Wts) protein kinase are activated is poorly understood. In this work, we found that the endogenous Mats is located at the plasma membrane in developing tissues. Membrane targeting constitutively activates Mats to promote apoptosis and reduce cell proliferation, which leads to reduced tissue growth and organ size. Moreover, the ability of membrane-targeted Mats to inhibit tissue growth required the wts gene activity and Wts kinase activity was increased by the activated Mats in developing tissues. Consistent with the idea that Mats is a key component of the Hpo pathway, Mats is required and sufficient to regulate Yki nuclear localization. These results support a model in which the plasma membrane is an important site of action for Mats tumor suppressor to control tissue growth and organ size.
Assuntos
Membrana Celular/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Drosophila melanogaster/crescimento & desenvolvimento , Proteínas Supressoras de Tumor/metabolismo , Animais , Apoptose , Núcleo Celular/metabolismo , Proliferação de Células , Células Cultivadas , Drosophila melanogaster/enzimologia , Drosophila melanogaster/ultraestrutura , Ativação Enzimática , Epistasia Genética , Olho/citologia , Olho/ultraestrutura , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Tamanho do Órgão , Especificidade de Órgãos , Ligação Proteica , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Transporte Proteico , Frações Subcelulares/metabolismoRESUMO
[This corrects the article DOI: 10.1371/journal.pone.0245454.].
RESUMO
Genome association studies in human and genetic studies in mouse implicated members of the transmembrane protein 132 (TMEM132) family in multiple conditions including panic disorder, hearing loss, limb and kidney malformation. However, the presence of five TMEM132 paralogs in mammalian genomes makes it extremely challenging to reveal the full requirement for these proteins in vivo. In contrast, there is only one TMEM132 homolog, detonator (dtn), in the genome of fruit fly Drosophila melanogaster, enabling straightforward research into its in vivo function. In the current study, we generate multiple loss-of-function dtn mutant fly strains through a polycistronic tRNA-gRNA approach, and show that most embryos lacking both maternal and paternal dtn fail to hatch into larvae, indicating an essential role of dtn in Drosophila reproduction.
Assuntos
Sistemas CRISPR-Cas , Drosophila melanogaster/genética , Edição de Genes , RNA Guia de Cinetoplastídeos/genética , RNA de Transferência/genética , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/fisiologia , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Proteínas de Drosophila/genética , Drosophila melanogaster/fisiologia , Feminino , Fertilidade , Edição de Genes/métodos , Mutação com Perda de Função , Masculino , ReproduçãoRESUMO
Studies in Drosophila have defined a new growth inhibitory pathway mediated by Fat (Ft), Merlin (Mer), Expanded (Ex), Hippo (Hpo), Salvador (Sav)/Shar-pei, Warts (Wts)/Large tumor suppressor (Lats), and Mob as tumor suppressor (Mats), which are all evolutionarily conserved in vertebrate animals. We previously found that the Mob family protein Mats functions as a coactivator of Wts kinase. Here we show that mats is essential for early development and is required for proper chromosomal segregation in developing embryos. Mats is expressed at low levels ubiquitously, which is consistent with the role of Mats as a general growth regulator. Like mammalian Mats, Drosophila Mats colocalizes with Wts/Lats kinase and cyclin E proteins at the centrosome. This raises the possibility that Mats may function together with Wts/Lats to regulate cyclin E activity in the centrosome for mitotic control. While Hpo/Wts signaling has been implicated in the control of cyclin E and diap1 expression, we found that it also modulates the expression of cyclin A and cyclin B. Although mats depletion leads to aberrant mitoses, this does not seem to be due to compromised mitotic spindle checkpoint function.
Assuntos
Drosophila/crescimento & desenvolvimento , Drosophila/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes Supressores de Tumor , Animais , Apoptose/genética , Ciclo Celular/genética , Genética Médica , Humanos , Neoplasias/genética , Neoplasias/veterinária , Saccharomyces cerevisiae/genéticaRESUMO
Protein-protein interactions provide a common mechanism for regulating protein functions and also serve as the fundamental step of many biochemical reactions. To accurately determine the involvement and function of protein-protein interactions, it is crucial to detect the interactions with the minimum number of artifacts. In this chapter, we report the method of bimolecular fluorescence complementation (BiFC) in tissue culture and developing tissues of Drosophila, which allows the visualization of subcellular localization of protein-protein interactions in living cells.
Assuntos
Drosophila/metabolismo , Imunofluorescência , Imagem Molecular , Mapeamento de Interação de Proteínas , Animais , Linhagem Celular , Drosophila/embriologia , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Expressão Gênica , Humanos , Discos Imaginais , Microscopia de Fluorescência/métodos , Imagem Molecular/métodos , Mapeamento de Interação de Proteínas/métodos , Técnicas de Cultura de Tecidos , Asas de AnimaisRESUMO
The considerable amount of experimental evidence has defined the Hippo pathway as a tumor suppressive pathway and increased expression and/or activity of its oncogenic effectors is frequently observed in cancer. However, clinical studies have failed to attribute cancer development and progression to mutations in the pathway. In explaining this conundrum, we investigated the expression and functions of a C-terminally truncated isoform of large tumor suppressor kinase 1 (LATS1) called short LATS1 (sLATS1) in human cell lines and Drosophila. Intriguingly, through overexpression of sLATS1, we demonstrated that sLATS1 either activates or suppresses the activity of Yes-associated protein (YAP), one of the effectors of the Hippo pathway, in a cell type-specific manner. The activation is mediated through inhibition of full-length LATS1, whereas suppression of YAP is accomplished through sLATS1-YAP interaction. In HEK293T cells, the former mechanism may affect the cellular response more dominantly, whereas in U2OS cells and developing tissues in Drosophila, the latter mechanism may be solely carried out. Finally, to find the clinical relevance of this molecule, we examined the expression of sLATS1 in breast cancer patients. The transcriptome analysis showed that the ratio of sLATS1 to LATS1 was increased in tumor tissues comparing to their adjacent normal tissues.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Western Blotting , Carcinogênese/metabolismo , Técnicas de Cultura de Células , Fracionamento Celular , Proliferação de Células/genética , Drosophila , Proteínas de Drosophila/metabolismo , Feminino , Citometria de Fluxo , Imunofluorescência , Células HEK293 , Via de Sinalização Hippo , Humanos , Imunoprecipitação , Proteínas Nucleares/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Transativadores/metabolismo , Fatores de Transcrição , Proteínas de Sinalização YAPRESUMO
In contrast to steady-state erythropoiesis, which generates new erythrocytes at a constant rate, stress erythropoiesis rapidly produces a large bolus of new erythrocytes in response to anemic stress. In this study, we illustrate that Yes-associated protein (Yap1) promotes the rapid expansion of a transit-amplifying population of stress erythroid progenitors in vivo and in vitro. Yap1-mutated erythroid progenitors failed to proliferate in the spleen after transplantation into lethally irradiated recipient mice. Additionally, loss of Yap1 impaired the growth of actively proliferating erythroid progenitors in vitro. This role in proliferation is supported by gene expression profiles showing that transiently amplifying stress erythroid progenitors express high levels of genes associated with Yap1 activity and genes induced by Yap1. Furthermore, Yap1 promotes the proliferation of stress erythroid progenitors in part by regulating the expression of key glutamine-metabolizing enzymes. Thus, Yap1 acts as an erythroid regulator that coordinates the metabolic status with the proliferation of erythroid progenitors to promote stress erythropoiesis.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas de Ciclo Celular/fisiologia , Células Precursoras Eritroides/fisiologia , Eritropoese/fisiologia , Regeneração/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Alelos , Animais , Divisão Celular , Células Cultivadas , Indução Enzimática , Células Precursoras Eritroides/citologia , Deleção de Genes , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/biossíntese , Quimera por Radiação , Tolerância a Radiação , Proteínas Recombinantes/metabolismo , Baço/citologia , Estresse Fisiológico/genética , Fatores de Transcrição/genética , Proteínas de Sinalização YAPRESUMO
Anemic stress induces the proliferation of stress erythroid progenitors in the murine spleen that subsequently differentiate to generate erythrocytes to maintain homeostasis. This process relies on the interaction between stress erythroid progenitors and the signals generated in the splenic erythroid niche. In this study, we demonstrate that although growth-differentiation factor 15 (Gdf15) is not required for steady-state erythropoiesis, it plays an essential role in stress erythropoiesis. Gdf15 acts at 2 levels. In the splenic niche, Gdf15-/- mice exhibit defects in the monocyte-derived expansion of the splenic niche, resulting in impaired proliferation of stress erythroid progenitors and production of stress burst forming unit-erythroid cells. Furthermore, Gdf15 signaling maintains the hypoxia-dependent expression of the niche signal, Bmp4, whereas in stress erythroid progenitors, Gdf15 signaling regulates the expression of metabolic enzymes, which contribute to the rapid proliferation of stress erythroid progenitors. Thus, Gdf15 functions as a comprehensive regulator that coordinates the stress erythroid microenvironment with the metabolic status of progenitors to promote stress erythropoiesis.
Assuntos
Células Precursoras Eritroides/metabolismo , Eritropoese/genética , Fator 15 de Diferenciação de Crescimento/genética , Nicho de Células-Tronco , Estresse Fisiológico , Animais , Diferenciação Celular , Proliferação de Células , Fator 15 de Diferenciação de Crescimento/metabolismo , Camundongos , Camundongos Knockout , Modelos Biológicos , Transdução de SinaisRESUMO
The Drosophila mats gene plays a critical role in growth control. Using molecular genetic approaches we investigated how mats is regulated in development. A 2236-bp genomic sequence that contains entire mats including upstream and downstream intergenic regions can rescue mats mutant phenotypes, indicating that regulatory elements necessary for proper mats expression are mostly retained. However, constructs without the upstream or downstream intergenic region failed to rescue mats mutants, demonstrating the functional importance of these sequences. Moreover, mats expression is reduced in mats(e17), a mats allele with over one-third of the downstream intergenic region deleted. Consistent with a model that the downstream intergenic region is critical for mats activity, this sequence contains evolutionarily conserved elements and has enhancer activities.
Assuntos
DNA Intergênico , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes Supressores de Tumor , Proteínas Supressoras de Tumor/genética , Alelos , Animais , Sequência de Bases , Drosophila melanogaster/crescimento & desenvolvimento , Deleção de SequênciaRESUMO
Receptor tyrosine kinase (RTK) signaling plays an instructive role in cell fate decisions, whereas Notch signaling is often involved in restricting cellular competence for differentiation. Genetic interactions between these two evolutionarily conserved pathways have been extensively documented. The underlying molecular mechanisms, however, are not well understood. Here, we show that Yan, an Ets transcriptional repressor that blocks cellular potential for specification and differentiation, is a target of Notch signaling during Drosophila eye development. The Suppressor of Hairless (Su[H]) protein of the Notch pathway is required for activating yan expression, and Su(H) binds directly to an eye-specific yan enhancer in vitro. In contrast, yan expression is repressed by Pointed (Pnt), which is a key component of the RTK pathway. Pnt binds specifically to the yan enhancer and competes with Su(H) for DNA binding. This competition illustrates a potential mechanism for RTK and Notch signals to oppose each other. Thus, yan serves as a common target of Notch/Su(H) and RTK/Pointed signaling pathways during cell fate specification.
Assuntos
Proteínas de Drosophila , Proteínas do Olho/genética , Regulação da Expressão Gênica , Proteínas de Membrana/metabolismo , Proteínas , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Animais , Sequência de Bases , Proteínas de Ligação a DNA , Drosophila melanogaster , Elementos Facilitadores Genéticos , Dados de Sequência Molecular , Proteínas do Tecido Nervoso , Receptores Notch , Fatores de TranscriçãoRESUMO
Tumour metastasis is a significant contributor to death in cancer patients. So studies on the molecular mechanism of tumor metastasis can provide new prognostic and therapeutic methods. Tumor metastasis suppressor gene is a kind of genes that only suppresses metastasis without affecting tumorigenicity and tumor growth. BRMS1 is a tumor metastasis suppressor gene discovered in breast carcinoma cells in 2000. Its protein product was found to also suppress metastasis of melanoma cells and murine mammary carcinoma cells. BRMS1 is located in the nucleus,and interacts with mSin3-HDAC complex, and can alter the connexin expression profile of breast carcinoma cells, thereby restoring cell-cell communication via gap junctions. This review highlights some recent progress in the study of BRMS1, gives a brief introduction of related genes, and predicts its possible mechanism of action.
Assuntos
Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Animais , Sequência de Bases , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Humanos , Metástase Neoplásica/genética , Receptores de Estrogênio/metabolismo , Proteínas RepressorasRESUMO
Mammalian pancreatic ß-cells play a pivotal role in development and glucose homeostasis through the production and secretion of insulin. Functional failure or decrease in ß-cell number leads to type 2 diabetes (T2D). Despite the physiological importance of ß-cells, the viability of ß-cells is often challenged mainly due to its poor ability to adapt to their changing microenvironment. One of the factors that negatively affect ß-cell viability is high concentration of free fatty acids (FFAs) such as palmitate. In this work, we demonstrated that Yes-associated protein (Yap1) is activated when ß-cells are treated with palmitate. Our loss- and gain-of-function analyses using rodent insulinoma cell lines revealed that Yap1 suppresses palmitate-induced apoptosis in ß-cells without regulating their proliferation. We also found that upon palmitate treatment, re-arrangement of F-actin mediates Yap1 activation. Palmitate treatment increases expression of one of the Yap1 target genes, connective tissue growth factor (CTGF). Our gain-of-function analysis with CTGF suggests CTGF may be the downstream factor of Yap1 in the protective mechanism against FFA-induced apoptosis.