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1.
Lancet Oncol ; 15(13): 1469-1480, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25456366

RESUMO

BACKGROUND: Improved clinical predictors for disease progression are needed for localised prostate cancer, since only a subset of patients develop recurrent or refractory disease after first-line treatment. Therefore, we undertook an unbiased analysis to identify RNA biomarkers associated with metastatic progression after prostatectomy. METHODS: Prostate cancer samples from patients treated with radical prostatectomy at three academic institutions were analysed for gene expression by a high-density Affymetrix GeneChip platform, encompassing more than 1 million genomic loci. In a discovery cohort, all protein-coding genes and known long non-coding RNAs were ranked by fold change in expression between tumours that subsequently metastasised versus those that did not. The top ranked gene was then validated for its prognostic value for metastatic progression in three additional independent cohorts. 95% of the gene expression assays were done in a Clinical Laboratory Improvements Amendments certified laboratory facility. All genes were assessed for their ability to predict metastatic progression by receiver-operating-curve area-under-the-curve analyses. Multivariate analyses were done for the primary endpoint of metastatic progression, with variables including Gleason score, preoperative prostate-specific antigen concentration, seminal vesicle invasion, surgical margin status, extracapsular extension, lymph node invasion, and expression of the highest ranked gene. FINDINGS: 1008 patients were included in the study: 545 in the discovery cohort and 463 in the validation cohorts. The long non-coding RNA SChLAP1 was identified as the highest-ranked overexpressed gene in cancers with metastatic progression. Validation in three independent cohorts confirmed the prognostic value of SChLAP1 for metastatic progression. On multivariate modelling, SChLAP1 expression (high vs low) independently predicted metastasis within 10 years (odds ratio [OR] 2·45, 95% CI 1·70-3·53; p<0·0001). The only other variable that independently predicted metastasis within 10 years was Gleason score (8-10 vs 5-7; OR 2·14, 95% CI 1·77-2·58; p<0·0001). INTERPRETATION: We identified and validated high SChLAP1 expression as significantly prognostic for metastatic disease progression of prostate cancer. Our findings suggest that further development of SChLAP1 as a potential biomarker, for treatment intensification in aggressive prostate cancer, warrants future study. FUNDING: Prostate Cancer Foundation, National Institutes of Health, Department of Defense, Early Detection Research Network, Doris Duke Charitable Foundation, and Howard Hughes Medical Institute.


Assuntos
Biomarcadores Tumorais/genética , Sequenciamento de Nucleotídeos em Larga Escala , Recidiva Local de Neoplasia/genética , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Idoso , Estudos de Casos e Controles , Progressão da Doença , Seguimentos , Perfilação da Expressão Gênica , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Prognóstico , Antígeno Prostático Específico/sangue , Prostatectomia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/cirurgia , Estudos Retrospectivos , Taxa de Sobrevida
2.
Nucleic Acids Res ; 37(7): 2142-52, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19223330

RESUMO

Giant chromatin-modifying complexes regulate gene transcription in eukaryotes by acting on chromatin substrates and 'setting' the histone code. The histone deacetylase (HDAC)-associated mammalian Sin3 corepressor complex regulates a wide variety of genes involved in all aspects of cellular physiology. The recruitment of the corepressor complex by transcription factors to specific regions of the genome is mediated by Sin3 as well as 10 distinct polypeptides that comprise the corepressor complex. Here we report the solution structure of a novel CCCH zinc finger (ZnF) motif in the SAP30 polypeptide, a key component of the corepressor complex. The structure represents a novel fold comprising two beta-strands and two alpha-helices with the zinc organizing center showing remote resemblance to the treble clef motif. In silico analysis of the structure revealed a highly conserved surface that is dominated by basic residues. NMR-based analysis of potential ligands for the SAP30 ZnF motif indicated a strong preference for nucleic acid substrates. We propose that the SAP30 ZnF functions as a double-stranded DNA-binding motif, thereby expanding the known functions of both SAP30 and the mammalian Sin3 corepressor complex. Our results also call into question the common assumption about the exclusion of DNA-binding core subunits within chromatin-modifying/remodeling complexes.


Assuntos
Proteínas de Ligação a DNA/química , Histona Desacetilases/química , Proteínas Repressoras/química , Dedos de Zinco , Sequência de Aminoácidos , DNA/química , DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Histona Desacetilases/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Ressonância Magnética Nuclear Biomolecular , Proteínas Nucleares/química , Ligação Proteica , Dobramento de Proteína , Proteínas Repressoras/metabolismo , Complexo Correpressor Histona Desacetilase e Sin3 , Relação Estrutura-Atividade , Fatores de Transcrição/química
3.
A A Pract ; 15(8): e01508, 2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34388136

RESUMO

The trigeminocardiac reflex (TCR) is triggered by stimulation of a branch of the trigeminal nerve and results in vagally mediated bradycardia, hypotension, apnea, and gastrointestinal hypermotility. In the operating theatre, patients susceptible to TCR are typically under general anesthesia; thus, cardiac abnormalities are the most common manifestation. Our case highlights the less common intraoperative manifestations of gastric hypermotility and apnea in a patient undergoing awake craniotomy for tumor resection. Prompt recognition, removal of stimuli, and airway management prevented catastrophic complications while facilitating completion of the procedure.


Assuntos
Reflexo Trigêmino-Cardíaco , Bradicardia/etiologia , Craniotomia/efeitos adversos , Humanos , Complicações Intraoperatórias/etiologia , Vigília
4.
Trends Cancer ; 1(2): 93-109, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26693181

RESUMO

While our understanding of the molecular mechanisms underlying cancer has significantly improved, most of our knowledge focuses on protein-coding genes that make up a fraction of the genome. Recent studies have uncovered thousands of long noncoding RNAs (lncRNAs) that populate the cancer genome. A subset of these molecules shows striking cancer- and lineage-specific expression patterns, suggesting they may be potential drivers of cancer biology and have utility as clinical biomarkers. Here, we discuss emerging modalities of lncRNA biology and their interplay with cancer-associated concepts, including epigenetic regulation, DNA damage and cell cycle control, microRNA silencing, signal transduction pathways, and hormone-driven disease. Additionally, we highlight the translational impact of lncRNAs, tools for their mechanistic investigation, and directions for future lncRNA research.

5.
Nat Genet ; 47(3): 199-208, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25599403

RESUMO

Long noncoding RNAs (lncRNAs) are emerging as important regulators of tissue physiology and disease processes including cancer. To delineate genome-wide lncRNA expression, we curated 7,256 RNA sequencing (RNA-seq) libraries from tumors, normal tissues and cell lines comprising over 43 Tb of sequence from 25 independent studies. We applied ab initio assembly methodology to this data set, yielding a consensus human transcriptome of 91,013 expressed genes. Over 68% (58,648) of genes were classified as lncRNAs, of which 79% were previously unannotated. About 1% (597) of the lncRNAs harbored ultraconserved elements, and 7% (3,900) overlapped disease-associated SNPs. To prioritize lineage-specific, disease-associated lncRNA expression, we employed non-parametric differential expression testing and nominated 7,942 lineage- or cancer-associated lncRNA genes. The lncRNA landscape characterized here may shed light on normal biology and cancer pathogenesis and may be valuable for future biomarker development.


Assuntos
RNA Longo não Codificante/genética , Transcriptoma , Linhagem Celular , Linhagem Celular Tumoral , Expressão Gênica , Humanos , Neoplasias/genética , Análise de Sequência de RNA/métodos
6.
Neoplasia ; 16(12): 1121-7, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25499224

RESUMO

Long noncoding RNAs (lncRNAs) are an emerging class of oncogenic molecules implicated in a diverse range of human malignancies. We recently identified SChLAP1 as a novel lncRNA that demonstrates outlier expression in a subset of prostate cancers, promotes tumor cell invasion and metastasis, and associates with lethal disease. Based on these findings, we sought to develop an RNA in situ hybridization (ISH) assay for SChLAP1 to 1) investigate the spectrum of SChLAP1 expression from benign prostatic tissue to metastatic castration-resistant prostate cancer and 2) to determine whether SChLAP1 expression by ISH is associated with outcome after radical prostatectomy in patients with clinically localized disease. The results from our current study demonstrate that SChLAP1 expression increases with prostate cancer progression, and high SChLAP1 expression by ISH is associated with poor outcome after radical prostatectomy in patients with clinically localized prostate cancer by both univariate (hazard ratio = 2.343, P = .005) and multivariate (hazard ratio = 1.99, P = .032) Cox regression analyses. This study highlights a potential clinical utility for SChLAP1 ISH as a novel tissue-based biomarker assay for outcome prognostication after radical prostatectomy.


Assuntos
Biomarcadores Tumorais/genética , Hibridização In Situ/métodos , Proteínas de Neoplasias/genética , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , RNA/genética , Humanos , Masculino , Prostatectomia
7.
Oncotarget ; 5(6): 1434-8, 2014 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-24727738

RESUMO

Long noncoding RNAs (IncRNAs) are increasingly implicated in cancer biology, contributing to essential cancer cell functions such as proliferation, invasion, and metastasis. In prostate cancer, several lncRNAs have been nominated as critical actors in disease pathogenesis. Among these, expression of PCGEM1 and PRNCR1 has been identified as a possible component in disease progression through the coordination of androgen receptor (AR) signaling (Yang et al., Nature 2013, see ref. [1]). However, concerns regarding the robustness of these findings have been suggested. Here, we sought to evaluate whether PCGEM1 and PRNCR1 are associated with prostate cancer. Through a comprehensive analysis of RNA-sequencing data (RNA-seq), we find evidence that PCGEM1 but not PRNCR1 is associated with prostate cancer. We employ a large cohort of >230 high-risk prostate cancer patients with long-term outcomes data to show that, in contrast to prior reports, neither gene is associated with poor patient outcomes. We further observe no evidence that PCGEM1 nor PRNCR1 interact with AR, and neither gene is a component of AR signaling. Thus, we conclusively demonstrate that PCGEM1 and PRNCR1 are not prognostic lncRNAs in prostate cancer and we refute suggestions that these lncRNAs interact in AR signaling.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias de Próstata Resistentes à Castração/genética , RNA Longo não Codificante/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Proteínas de Neoplasias/genética , Prognóstico , Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/mortalidade , Receptores Androgênicos/genética
8.
Mol Cancer Res ; 12(8): 1081-7, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25030374

RESUMO

UNLABELLED: Long noncoding RNAs (lncRNA) have recently been associated with the development and progression of a variety of human cancers. However, to date, the interplay between known oncogenic or tumor-suppressive events and lncRNAs has not been well described. Here, the novel lncRNA, prostate cancer-associated transcript 29 (PCAT29), is characterized along with its relationship to the androgen receptor. PCAT29 is suppressed by DHT and upregulated upon castration therapy in a prostate cancer xenograft model. PCAT29 knockdown significantly increased proliferation and migration of prostate cancer cells, whereas PCAT29 overexpression conferred the opposite effect and suppressed growth and metastases of prostate tumors in chick chorioallantoic membrane assays. Finally, in prostate cancer patient specimens, low PCAT29 expression correlated with poor prognostic outcomes. Taken together, these data expose PCAT29 as an androgen-regulated tumor suppressor in prostate cancer. IMPLICATIONS: This study identifies PCAT29 as the first androgen receptor-repressed lncRNA that functions as a tumor suppressor and that its loss may identify a subset of patients at higher risk for disease recurrence. Visual Overview: http://mcr.aacrjournals.org/content/early/2014/07/31/1541-7786.MCR-14-0257/F1.large.jpg.


Assuntos
Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Proteínas Supressoras de Tumor/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fenótipo , Neoplasias da Próstata/patologia
9.
Cancer Res ; 74(6): 1651-60, 2014 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-24473064

RESUMO

Impairment of double-stranded DNA break (DSB) repair is essential to many cancers. However, although mutations in DSB repair proteins are common in hereditary cancers, mechanisms of impaired DSB repair in sporadic cancers remain incompletely understood. Here, we describe the first role for a long noncoding RNA (lncRNA) in DSB repair in prostate cancer. We identify PCAT-1, a prostate cancer outlier lncRNA, which regulates cell response to genotoxic stress. PCAT-1 expression produces a functional deficiency in homologous recombination through its repression of the BRCA2 tumor suppressor, which, in turn, imparts a high sensitivity to small-molecule inhibitors of PARP1. These effects reflected a posttranscriptional repression of the BRCA2 3'UTR by PCAT-1. Our observations thus offer a novel mechanism of "BRCAness" in sporadic cancers.


Assuntos
Proteína BRCA2/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Reparo de DNA por Recombinação , Regiões 3' não Traduzidas , Animais , Antineoplásicos/farmacologia , Proteína BRCA2/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Dano ao DNA , Humanos , Masculino , Camundongos , Camundongos SCID , Ftalazinas/farmacologia , Piperazinas/farmacologia , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases , Poli(ADP-Ribose) Polimerases/metabolismo , Neoplasias da Próstata/metabolismo , Interferência de RNA , RNA Longo não Codificante/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Nat Commun ; 4: 2617, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24135919

RESUMO

Global 'multi-omics' profiling of cancer cells harbours the potential for characterizing the signalling networks associated with specific oncogenes. Here we profile the transcriptome, proteome and phosphoproteome in a panel of non-small cell lung cancer (NSCLC) cell lines in order to reconstruct targetable networks associated with KRAS dependency. We develop a two-step bioinformatics strategy addressing the challenge of integrating these disparate data sets. We first define an 'abundance-score' combining transcript, protein and phospho-protein abundances to nominate differentially abundant proteins and then use the Prize Collecting Steiner Tree algorithm to identify functional sub-networks. We identify three modules centred on KRAS and MET, LCK and PAK1 and ß-Catenin. We validate activation of these proteins in KRAS-dependent (KRAS-Dep) cells and perform functional studies defining LCK as a critical gene for cell proliferation in KRAS-Dep but not KRAS-independent NSCLCs. These results suggest that LCK is a potential druggable target protein in KRAS-Dep lung cancers.


Assuntos
Antineoplásicos/farmacologia , Biologia Computacional , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/genética , Fosfoproteínas/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Algoritmos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Redes Reguladoras de Genes , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Terapia de Alvo Molecular , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Transdução de Sinais , Transcriptoma , beta Catenina/genética , beta Catenina/metabolismo , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo , Proteínas ras/metabolismo
11.
Nat Genet ; 45(11): 1392-8, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24076601

RESUMO

Prostate cancers remain indolent in the majority of individuals but behave aggressively in a minority. The molecular basis for this clinical heterogeneity remains incompletely understood. Here we characterize a long noncoding RNA termed SChLAP1 (second chromosome locus associated with prostate-1; also called LINC00913) that is overexpressed in a subset of prostate cancers. SChLAP1 levels independently predict poor outcomes, including metastasis and prostate cancer-specific mortality. In vitro and in vivo gain-of-function and loss-of-function experiments indicate that SChLAP1 is critical for cancer cell invasiveness and metastasis. Mechanistically, SChLAP1 antagonizes the genome-wide localization and regulatory functions of the SWI/SNF chromatin-modifying complex. These results suggest that SChLAP1 contributes to the development of lethal cancer at least in part by antagonizing the tumor-suppressive functions of the SWI/SNF complex.


Assuntos
Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/genética , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Regiões Promotoras Genéticas , Interferência de RNA , RNA Interferente Pequeno , Proteína SMARCB1
12.
Mol Cancer Ther ; 11(6): 1236-46, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22491800

RESUMO

G-protein-coupled receptors (GPCR) activate the epidermal growth factor receptor (EGFR) and mediate EGFR-independent signaling pathways to promote the growth of a variety of cancers, including head and neck squamous cell carcinoma (HNSCC). Identification of the common signaling mechanisms involved in GPCR-induced EGFR-dependent and EGFR-independent processes will facilitate the development of more therapeutic strategies. In this study, we hypothesized that phosphoinositide-dependent kinase 1 (PDK1) contributes to GPCR-EGFR cross-talk and signaling in the absence of EGFR and suggests that inhibition of the PDK1 pathway may be effective in the treatment of HNSCC. The contribution of PDK1 to the EGFR-dependent and EGFR-independent signaling in HNSCC was determined using RNA interference, a kinase-dead mutant, and pharmacologic inhibition. In vivo xenografts studies were also carried out to determine the efficacy of targeting PDK1 alone or in combination with the U.S. Food and Drug Administration-approved EGFR inhibitor cetuximab. PDK1 contributed to both GPCR-induced EGFR activation and cell growth. PDK1 also mediated activation of p70S6K in the absence of EGFR. Blockade of PDK1 with a small molecule inhibitor (AR-12) abrogated HNSCC growth, induced apoptosis, and enhanced the antiproliferative effects of EGFR tyrosine kinase inhibitors in vitro. HNSCC xenografts expressing kinase-dead PDK1 showed increased sensitivity to cetuximab compared with vector-transfected controls. Administration of AR-12 substantially decreased HNSCC tumor growth in vivo. These cumulative results show that PDK1 is a common signaling intermediate in GPCR-EGFR cross-talk and EGFR-independent signaling, and in which targeting the PDK1 pathway may represent a rational therapeutic strategy to enhance clinical responses to EGFR inhibitors in HNSCC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Transdução de Sinais , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Anticorpos Monoclonais Humanizados/uso terapêutico , Apoptose , Carcinoma de Células Escamosas/enzimologia , Linhagem Celular Tumoral , Proliferação de Células , Cetuximab , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Neoplasias de Cabeça e Pescoço/enzimologia , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço
13.
Clin Cancer Res ; 17(15): 4996-5004, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21653688

RESUMO

PURPOSE: Epidermal growth factor receptor (EGFR) overexpression is correlated with decreased survival in head and neck cancer (HNC) where the addition of EGFR inhibition to standard chemoradiation approaches has improved treatment responses. However, the basis for the limited efficacy of EGFR inhibitors in HNC is incompletely understood. G-protein-coupled receptors (GPCR) have been shown to be overexpressed in HNC where GPCR activation induces HNC growth via both EGFR-dependent and -independent pathways. We hypothesized that targeting GPCR-induced EGFR-independent signaling would improve the efficacy of EGFR inhibition. EXPERIMENTAL DESIGN: Using a high-throughput phosphoproteome array, we identified proteins that were phosphorylated in HNC cells where EGFR expression was downmodulated by RNA interference (RNAi) in the presence or absence of a GPCR ligand. We confirmed the findings from the array by Western blotting followed by in vitro and in vivo phenotypic assays. RESULTS: p70S6K phosphorylation was elevated approximately sixfold in EGFR siRNA-transfected cells treated with a GPCR ligand. In addition to RNAi-mediated EGFR downmodulation, GPCR-mediated phosphorylation of p70S6K was modestly increased by EGFR inhibitor cetuximab approved by the Food and Drug Administration. Biopsies from cetuximab-treated patients also displayed increased phospho-p70S6K staining compared with pretreatment biopsies. HNC cells were growth inhibited by both genetic and pharmacologic p70S6K targeting strategies. Furthermore, p70S6K targeting in combination with cetuximab resulted in enhanced antitumor effects in both in vitro and in vivo HNC models. CONCLUSIONS: These results indicate that increased phosphorylation of p70S6K in cetuximab-treated patients may be due to increased GPCR signaling. Therefore, the addition of p70S6K targeting strategies may improve treatment responses to EGFR inhibition.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Anticorpos Monoclonais Humanizados , Linhagem Celular Tumoral , Cetuximab , Ativação Enzimática , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Ligantes , Terapia de Alvo Molecular , Fosforilação , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo
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