Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 15 de 15
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Oncol ; 2023 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-37452637

RESUMO

Nutrient availability is a key determinant of tumor cell behavior. While nutrient-rich conditions favor proliferation and tumor growth, scarcity, and particularly glutamine starvation, promotes cell dedifferentiation and chemoresistance. Here, linking ribosome biogenesis plasticity with tumor cell fate, we uncover that the amino acid sensor general control non-derepressible 2 (GCN2; also known as eIF-2-alpha kinase 4) represses the expression of the precursor of ribosomal RNA (rRNA), 47S, under metabolic stress. We show that blockade of GCN2 triggers cell death by an irremediable nucleolar stress and subsequent TP53-mediated apoptosis in patient-derived models of colon adenocarcinoma (COAD). In nutrient-rich conditions, a cell-autonomous GCN2 activity supports cell proliferation by stimulating 47S rRNA transcription, independently of the canonical integrated stress response (ISR) axis. Impairment of GCN2 activity prevents nuclear translocation of methionyl-tRNA synthetase (MetRS), resulting in nucleolar stress, mTORC1 inhibition and, ultimately, autophagy induction. Inhibition of the GCN2-MetRS axis drastically improves the cytotoxicity of RNA polymerase I (RNA pol I) inhibitors, including the first-line chemotherapy oxaliplatin, on patient-derived COAD tumoroids. Our data thus reveal that GCN2 differentially controls ribosome biogenesis according to the nutritional context. Furthermore, pharmacological co-inhibition of the two GCN2 branches and RNA pol I activity may represent a valuable strategy for elimination of proliferative and metabolically stressed COAD cells.

2.
FEBS J ; 2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36516350

RESUMO

Advances in cancer biology over the past decades have revealed that metabolic adaptation of cancer cells is an essential aspect of tumorigenesis. However, recent insights into tumour metabolism in vivo have revealed dissimilarities with results obtained in vitro. This is partly due to the reductionism of in vitro cancer models that struggle to reproduce the complexity of tumour tissues. This review describes some of the discrepancies in cancer cell metabolism between in vitro and in vivo conditions, and presents current methodological approaches and tools used to bridge the gap with the clinically relevant microenvironment. As such, these approaches should generate new knowledge that could be more effectively translated into therapeutic opportunities.

3.
Life Sci Alliance ; 5(7)2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35396334

RESUMO

The glucose-requiring hexosamine biosynthetic pathway (HBP), which produces UDP-N-acetylglucosamine for glycosylation reactions, promotes lung adenocarcinoma (LUAD) progression. However, lung tumor cells often reside in low-nutrient microenvironments, and whether the HBP is involved in the adaptation of LUAD to nutrient stress is unknown. Here, we show that the HBP and the coat complex II (COPII) play a key role in cell survival during glucose shortage. HBP up-regulation withstood low glucose-induced production of proteins bearing truncated N-glycans, in the endoplasmic reticulum. This function for the HBP, alongside COPII up-regulation, rescued cell surface expression of a subset of glycoproteins. Those included the epidermal growth factor receptor (EGFR), allowing an EGFR-dependent cell survival under low glucose in anchorage-independent growth. Accordingly, high expression of the HBP rate-limiting enzyme GFAT1 was associated with wild-type EGFR activation in LUAD patient samples. Notably, HBP and COPII up-regulation distinguished LUAD from the lung squamous-cell carcinoma subtype, thus uncovering adaptive mechanisms of LUAD to their harsh microenvironment.


Assuntos
Glucose , Hexosaminas , Receptores ErbB/genética , Glucose/metabolismo , Glicosilação , Hexosaminas/metabolismo , Humanos , Nutrientes
4.
Metabolites ; 11(4)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810430

RESUMO

Genetic alterations in non-small cell lung cancers (NSCLC) stimulate the generation of energy and biomass to promote tumor development. However, the efficacy of the translation process is finely regulated by stress sensors, themselves often controlled by nutrient availability and chemotoxic agents. Yet, the crosstalk between therapeutic treatment and glucose availability on cell mass generation remains understudied. Herein, we investigated the impact of pemetrexed (PEM) treatment, a first-line agent for NSCLC, on protein synthesis, depending on high or low glucose availability. PEM treatment drastically repressed cell mass and translation when glucose was abundant. Surprisingly, inhibition of protein synthesis caused by low glucose levels was partially dampened upon co-treatment with PEM. Moreover, PEM counteracted the elevation of the endoplasmic reticulum stress (ERS) signal produced upon low glucose availability, providing a molecular explanation for the differential impact of the drug on translation according to glucose levels. Collectively, these data indicate that the ERS constitutes a molecular crosstalk between microenvironmental stressors, contributing to translation reprogramming and proteostasis plasticity.

5.
iScience ; 23(6): 101141, 2020 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-32450513

RESUMO

Epigenetic deregulation of gene transcription is central to cancer cell plasticity and malignant progression but remains poorly understood. We found that the uncharacterized epigenetic factor chromodomain on Y-like 2 (CDYL2) is commonly over-expressed in breast cancer, and that high CDYL2 levels correlate with poor prognosis. Supporting a functional role for CDYL2 in malignancy, it positively regulated breast cancer cell migration, invasion, stem-like phenotypes, and epithelial-to-mesenchymal transition. CDYL2 regulation of these plasticity-associated processes depended on signaling via p65/NF-κB and STAT3. This, in turn, was downstream of CDYL2 regulation of MIR124 gene transcription. CDYL2 co-immunoprecipitated with G9a/EHMT2 and GLP/EHMT1 and regulated the chromatin enrichment of G9a and EZH2 at MIR124 genes. We propose that CDYL2 contributes to poor prognosis in breast cancer by recruiting G9a and EZH2 to epigenetically repress MIR124 genes, thereby promoting NF-κB and STAT3 signaling, as well as downstream cancer cell plasticity and malignant progression.

6.
Cancers (Basel) ; 12(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32121537

RESUMO

Endoplasmic reticulum (ER) stress generates reactive oxygen species (ROS) that induce apoptosis if left unabated. To limit oxidative insults, the ER stress PKR-like endoplasmic reticulum Kinase (PERK) has been reported to phosphorylate and activate nuclear factor erythroid 2-related factor 2 (NRF2). Here, we uncover an alternative mechanism for PERK-mediated NRF2 regulation in human cells that does not require direct phosphorylation. We show that the activation of the PERK pathway rapidly stimulates the expression of NRF2 through activating transcription factor 4 (ATF4). In addition, NRF2 activation is late and largely driven by reactive oxygen species (ROS) generated during late protein synthesis recovery, contributing to protecting against cell death. Thus, PERK-mediated NRF2 activation encompasses a PERK-ATF4-dependent control of NRF2 expression that contributes to the NRF2 protective response engaged during ER stress-induced ROS production.

7.
Sci Rep ; 6: 27278, 2016 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-27255611

RESUMO

The hexosamine biosynthetic pathway (HBP) is a nutrient-sensing metabolic pathway that produces the activated amino sugar UDP-N-acetylglucosamine, a critical substrate for protein glycosylation. Despite its biological significance, little is known about the regulation of HBP flux during nutrient limitation. Here, we report that amino acid or glucose shortage increase GFAT1 production, the first and rate-limiting enzyme of the HBP. GFAT1 is a transcriptional target of the activating transcription factor 4 (ATF4) induced by the GCN2-eIF2α signalling pathway. The increased production of GFAT1 stimulates HBP flux and results in an increase in O-linked ß-N-acetylglucosamine protein modifications. Taken together, these findings demonstrate that ATF4 provides a link between nutritional stress and the HBP for the regulation of the O-GlcNAcylation-dependent cellular signalling.


Assuntos
Fator 4 Ativador da Transcrição/metabolismo , Aminoácidos/metabolismo , Glucose/metabolismo , Hexosaminas/biossíntese , Proteínas Serina-Treonina Quinases/metabolismo , Acetilglucosamina/metabolismo , Animais , Vias Biossintéticas , Linhagem Celular , Células HeLa , Humanos , Camundongos , Transferases de Grupos Nitrogenados/metabolismo , Ratos , Transdução de Sinais
8.
Semin Cancer Biol ; 33: 34-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25931390

RESUMO

Both the hexosamine biosynthetic pathway (HBP) and the endoplasmic reticulum (ER) are considered sensors for the nutritional state of the cell. The former is a branch of the glucose metabolic pathway that provides donor molecules for glycosylation processes, whereas the second requires co-translational N-glycosylation to ensure proper protein folding. It has become clear that the microenvironment of solid tumours, characterised by poor oxygen and nutrient supply, challenges optimal functions of the ER and the HBP. Here, we review recent advances demonstrating that the ER stress (ERS) response and HBP pathways are interconnected to promote cell viability. We then develop the idea that communication between ER and HBP is a survival feature of neoplastic cells that plays a prominent role during tumourigenesis.


Assuntos
Estresse do Retículo Endoplasmático , Hexosaminas/metabolismo , Neoplasias/metabolismo , Animais , Carcinogênese , Linhagem da Célula , Sobrevivência Celular , Transformação Celular Neoplásica/metabolismo , Retículo Endoplasmático/metabolismo , Glucose/metabolismo , Glicosilação , Humanos , Neoplasias/fisiopatologia , Dobramento de Proteína , Microambiente Tumoral
9.
Proc Natl Acad Sci U S A ; 111(48): 17254-9, 2014 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-25404286

RESUMO

Inflammasomes are caspase-1-activating multiprotein complexes. The mouse nucleotide-binding domain and leucine rich repeat pyrin containing 1b (NLRP1b) inflammasome was identified as the sensor of Bacillus anthracis lethal toxin (LT) in mouse macrophages from sensitive strains such as BALB/c. Upon exposure to LT, the NLRP1b inflammasome activates caspase-1 to produce mature IL-1ß and induce pyroptosis. Both processes are believed to depend on autoproteolysed caspase-1. In contrast to human NLRP1, mouse NLRP1b lacks an N-terminal pyrin domain (PYD), indicating that the assembly of the NLRP1b inflammasome does not require the adaptor apoptosis-associated speck-like protein containing a CARD (ASC). LT-induced NLRP1b inflammasome activation was shown to be impaired upon inhibition of potassium efflux, which is known to play a major role in NLRP3 inflammasome formation and ASC dimerization. We investigated whether NLRP3 and/or ASC were required for caspase-1 activation upon LT stimulation in the BALB/c background. The NLRP1b inflammasome activation was assessed in both macrophages and dendritic cells lacking either ASC or NLRP3. Upon LT treatment, the absence of NLRP3 did not alter the NLRP1b inflammasome activity. Surprisingly, the absence of ASC resulted in IL-1ß cleavage and pyroptosis, despite the absence of caspase-1 autoprocessing activity. By reconstituting caspase-1/caspase-11(-/-) cells with a noncleavable or catalytically inactive mutant version of caspase-1, we directly demonstrated that noncleavable caspase-1 is fully active in response to the NLRP1b activator LT, whereas it is nonfunctional in response to the NLRP3 activator nigericin. Taken together, these results establish variable requirements for caspase-1 cleavage depending on the pathogen and the responding NLR.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Transporte/metabolismo , Caspase 1/metabolismo , Inflamassomos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proteínas Reguladoras de Apoptose/genética , Western Blotting , Proteínas Adaptadoras de Sinalização CARD , Proteínas de Transporte/genética , Caspase 1/genética , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Inflamassomos/genética , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Knockout , Camundongos Transgênicos , Microscopia de Fluorescência , Modelos Biológicos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Nigericina/farmacologia , Proteólise
10.
Am J Physiol Cell Physiol ; 307(10): C901-7, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25186011

RESUMO

The endoplasmic reticulum (ER)-induced unfolded protein response (UPR) is an adaptive mechanism that is activated upon accumulation of misfolded proteins in the ER and aims at restoring ER homeostasis. In the past 10 years, the UPR has emerged as an important actor in the different phases of tumor growth. The UPR is transduced by three major ER resident stress sensors, which are protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme-1 (IRE1). The signaling pathways elicited by those stress sensors have connections with metabolic pathways and with other plasma membrane receptor signaling networks. As such, the ER has an essential position as a signal integrator in the cell and is instrumental in the different phases of tumor progression. Herein, we describe and discuss the characteristics of an integrated signaling network that might condition the UPR biological outputs in a tissue- or stress-dependent manner. We discuss these issues in the context of the pathophysiological roles of UPR signaling in cancers.


Assuntos
Carcinogênese/metabolismo , Transformação Celular Neoplásica/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Transdução de Sinais/fisiologia , Resposta a Proteínas não Dobradas/fisiologia , Animais , Carcinogênese/patologia , Transformação Celular Neoplásica/patologia , Humanos
11.
Mol Cell ; 49(6): 1049-59, 2013 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-23395000

RESUMO

As solid tumors expand, oxygen and nutrients become limiting owing to inadequate vascularization and diffusion. How malignant cells cope with this potentially lethal metabolic stress remains poorly understood. We found that glucose shortage associated with malignant progression triggers apoptosis through the endoplasmic reticulum (ER) unfolded protein response (UPR). ER stress is in part caused by reduced glucose flux through the hexosamine pathway. Deletion of the proapoptotic UPR effector CHOP in a mouse model of K-ras(G12V)-induced lung cancer increases tumor incidence, strongly supporting the notion that ER stress serves as a barrier to malignancy. Overcoming this barrier requires the selective attenuation of the PERK-CHOP arm of the UPR by the molecular chaperone p58(IPK). Furthermore, p58(IPK)-mediated adaptive response enables cells to benefit from the protective features of chronic UPR. Altogether, these results show that ER stress activation and p58(IPK) expression control the fate of malignant cells facing glucose shortage.


Assuntos
Apoptose , Transformação Celular Neoplásica/metabolismo , Glucose/deficiência , Chaperonas Moleculares/fisiologia , Fator de Transcrição CHOP/metabolismo , eIF-2 Quinase/metabolismo , Acetilgalactosamina/metabolismo , Animais , Hipóxia Celular , Linhagem Celular , Proliferação de Células , Fator Neurotrófico Derivado de Linhagem de Célula Glial/fisiologia , Transportador de Glucose Tipo 1/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Ácido Láctico/metabolismo , Camundongos , Camundongos Nus , Transplante de Neoplasias , Proteínas Proto-Oncogênicas c-ret/metabolismo , Ratos , Resposta a Proteínas não Dobradas
12.
Cancer Res ; 72(6): 1449-58, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22271686

RESUMO

CD44 is a marker of cancer stem-like cells and epithelial-mesenchymal transition that is overexpressed in many cancer types, including thyroid carcinoma. At extracellular and intramembranous domains, CD44 undergoes sequential metalloprotease- and γ-secretase-mediated proteolytic cleavage, releasing the intracellular protein fragment CD44-ICD, which translocates to the nucleus and activates gene transcription. Here, we show that CD44-ICD binds to the transcription factor CREB, increasing S133 phosphorylation and CREB-mediated gene transcription. CD44-ICD enhanced CREB recruitment to the cyclin D1 promoter, promoting cyclin D1 transcription and cell proliferation. Thyroid carcinoma cells harboring activated RET/PTC, RAS, or BRAF oncogenes exhibited CD44 cleavage and CD44-ICD accumulation. Chemical blockade of RET/PTC, BRAF, metalloprotease, or γ-secretase were each sufficient to blunt CD44 processing. Furthermore, thyroid cancer cell proliferation was obstructed by RNA interference-mediated knockdown of CD44 or inhibition of γ-secretase and adoptive CD44-ICD overexpression rescued cell proliferation. Together, these findings reveal a CD44-CREB signaling pathway that is needed to sustain cancer cell proliferation, potentially offering new molecular targets for therapeutic intervention in thyroid carcinoma.


Assuntos
Carcinoma Papilar/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Receptores de Hialuronatos/metabolismo , Proteólise , Neoplasias da Glândula Tireoide/patologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Animais , Carcinoma Papilar/genética , Carcinoma Papilar/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Ciclina D1/genética , Ciclina D1/metabolismo , Humanos , Metaloproteases/antagonistas & inibidores , Metaloproteases/genética , Oncogenes/efeitos dos fármacos , Fosforilação , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Ratos , Transdução de Sinais , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Transcrição Gênica
13.
PLoS One ; 5(6): e10977, 2010 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-20544018

RESUMO

BACKGROUND: Cellular cholesterol is a vital component of the cell membrane. Its concentration is tightly controlled by mechanisms that remain only partially characterized. In this study, we describe a late endosome/lysosomes-associated protein whose expression level affects cellular free cholesterol content. METHODOLOGY/PRINCIPAL FINDINGS: Using a restricted proteomic analysis of detergent-resistant membranes (DRMs), we have identified a protein encoded by gene C11orf59. It is mainly localized to late endosome/lysosome (LE/LY) compartment through N-terminal myristoylation and palmitoylation. We named it Pdro for protein associated with DRMs and endosomes. Very recently, three studies have reported on the same protein under two other names: the human p27RF-Rho that regulates RhoA activation and actin dynamics, and its rodent orthologue p18 that controls both LE/LY dynamics through the MERK-ERK pathway and the lysosomal activation of mammalian target of rapamycin complex 1 by amino acids. We found that, consistent with the presence of sterol-responsive element consensus sequences in the promoter region of C11orf59, Pdro mRNA and protein expression levels are regulated positively by cellular cholesterol depletion and negatively by cellular cholesterol loading. Conversely, Pdro is involved in the regulation of cholesterol homeostasis, since its depletion by siRNA increases cellular free cholesterol content that is accompanied by an increased cholesterol efflux from cells. On the other hand, cells stably overexpressing Pdro display reduced cellular free cholesterol content. Pdro depletion-mediated excess cholesterol results, at least in part, from a stimulated low-density lipoprotein (LDL) uptake and an increased cholesterol egress from LE/LY. CONCLUSIONS/SIGNIFICANCE: LDL-derived cholesterol release involves LE/LY motility that is linked to actin dynamics. Because Pdro regulates these two processes, we propose that modulation of Pdro expression in response to sterol levels regulates LDL-derived cholesterol through both LDL uptake and LE/LY dynamics, to ultimately control free cholesterol homeostasis.


Assuntos
Proteínas de Transporte/metabolismo , Colesterol/metabolismo , Endossomos/metabolismo , Homeostase , Lisossomos/metabolismo , Sequência de Aminoácidos , Sequência de Bases , Transporte Biológico , Proteínas de Transporte/química , Proteínas de Transporte/genética , Primers do DNA , Citometria de Fluxo , Imunofluorescência , Técnicas de Silenciamento de Genes , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Lipoproteínas LDL/metabolismo , Dados de Sequência Molecular , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espectrometria de Massas em Tandem
14.
Cancer Res ; 66(7): 3681-7, 2006 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-16585194

RESUMO

The metalloprotease-dependent extracellular domain cleavage of the adhesion molecule CD44 is frequently observed in human tumors and is thought to promote metastasis. This cleavage is followed by gamma-secretase-dependent release of CD44 intracellular domain (CD44-ICD), which exhibits nuclear signaling activity. Using a reversible Ret-dependent oncogenic conversion model and a restricted proteomic approach, we identified a positive correlation between the neoplastic transformation of Rat-1 cells and the expression of standard CD44. In these transformed cells, CD44 was found to undergo a sequential metalloprotease and gamma-secretase cleavage, resulting in an increase in expression of CD44-ICD. We showed that this proteolytic fragment possesses a transforming activity. In support of this role, a significant and specific reduction in Ret-induced transformation of Rat-1 cells was observed following drug-mediated inhibition of gamma-secretase. Taken together, these findings suggest that the shedding of CD44 may not only modulate metastasis but also affects earlier events in tumorigenesis through the release of CD44-ICD.


Assuntos
Transformação Celular Neoplásica/metabolismo , Endopeptidases/metabolismo , Receptores de Hialuronatos/metabolismo , Sequência de Aminoácidos , Secretases da Proteína Precursora do Amiloide , Animais , Ácido Aspártico Endopeptidases , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Transformação Celular Neoplásica/genética , Detergentes/farmacologia , Fibroblastos/enzimologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Receptores de Hialuronatos/biossíntese , Receptores de Hialuronatos/genética , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Isoformas de Proteínas , Estrutura Terciária de Proteína , Ratos , Regulação para Cima
15.
J Biol Chem ; 280(44): 36584-91, 2005 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-16123037

RESUMO

Dominant-activating mutations in the RET (rearranged during transfection) proto-oncogene, a receptor tyrosine kinase, are causally associated with the development of multiple endocrine neoplasia type 2A (MEN2A) syndrome. Such oncogenic RET mutations induce its ligand-independent constitutive activation, but whether it spreads identical signaling to ligand-induced signaling is uncertain. To address this question, we designed a cellular model in which RET can be activated either by its natural ligand, or alternatively, by controlled dimerization of the protein that mimics MEN2A dimerization. We have shown that controlled dimerization leaves proximal RET signaling intact but impacts substantially on the tuning of the distal AKT kinase activation (delayed and sustained). In marked contrast, distal activation of ERK remained unaffected. We further demonstrated that specific temporal adjustment of ligand-induced AKT activation is dependent upon a lipid-based cholesterol-sensitive environment, and this control step is bypassed by MEN2A RET mutants. Therefore, these studies revealed that MEN2A mutations propagate previously unappreciated subtle differences in signaling pathways and unravel a role for lipid rafts in the temporal regulation of AKT activation.


Assuntos
Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Neoplasia Endócrina Múltipla Tipo 2a/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Transdução de Sinais , Dimerização , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Humanos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Mutação , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-ret/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...