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1.
Cell ; 157(4): 869-81, 2014 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-24813610

RESUMO

Fragile X syndrome, a common form of inherited intellectual disability, is caused by loss of the fragile X mental retardation protein FMRP. FMRP is present predominantly in the cytoplasm, where it regulates translation of proteins that are important for synaptic function. We identify FMRP as a chromatin-binding protein that functions in the DNA damage response (DDR). Specifically, we show that FMRP binds chromatin through its tandem Tudor (Agenet) domain in vitro and associates with chromatin in vivo. We also demonstrate that FMRP participates in the DDR in a chromatin-binding-dependent manner. The DDR machinery is known to play important roles in developmental processes such as gametogenesis. We show that FMRP occupies meiotic chromosomes and regulates the dynamics of the DDR machinery during mouse spermatogenesis. These findings suggest that nuclear FMRP regulates genomic stability at the chromatin interface and may impact gametogenesis and some developmental aspects of fragile X syndrome.


Assuntos
Espermatogênese , Animais , Cromatina/metabolismo , Pareamento Cromossômico , Dano ao DNA , Embrião de Mamíferos/citologia , Fibroblastos , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Hipocampo/citologia , Histonas/metabolismo , Humanos , Masculino , Meiose , Camundongos , Camundongos Knockout , Mutação , Neurônios/metabolismo , Prófase , Receptores de AMPA/metabolismo
2.
Mol Cell ; 78(6): 1133-1151.e14, 2020 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-32402252

RESUMO

Precise control of the RNA polymerase II (RNA Pol II) cycle, including pausing and pause release, maintains transcriptional homeostasis and organismal functions. Despite previous work to understand individual transcription steps, we reveal a mechanism that integrates RNA Pol II cycle transitions. Surprisingly, KAP1/TRIM28 uses a previously uncharacterized chromatin reader cassette to bind hypo-acetylated histone 4 tails at promoters, guaranteeing continuous progression of RNA Pol II entry to and exit from the pause state. Upon chromatin docking, KAP1 first associates with RNA Pol II and then recruits a pathway-specific transcription factor (SMAD2) in response to cognate ligands, enabling gene-selective CDK9-dependent pause release. This coupling mechanism is exploited by tumor cells to aberrantly sustain transcriptional programs commonly dysregulated in cancer patients. The discovery of a factor integrating transcription steps expands the functional repertoire by which chromatin readers operate and provides mechanistic understanding of transcription regulation, offering alternative therapeutic opportunities to target transcriptional dysregulation.


Assuntos
RNA Polimerase II/metabolismo , Proteína 28 com Motivo Tripartido/metabolismo , Acetilação , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Quinase 9 Dependente de Ciclina/metabolismo , Regulação da Expressão Gênica/genética , Histonas/metabolismo , Humanos , Oncogenes/genética , Regiões Promotoras Genéticas/genética , Processamento de Proteína Pós-Traducional/genética , RNA Polimerase II/genética , Proteína Smad2/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Gênica , Proteína 28 com Motivo Tripartido/genética
3.
Trends Biochem Sci ; 48(7): 610-617, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37061424

RESUMO

Plant homeodomain (PHD) fingers comprise a large and well-established family of epigenetic readers that recognize histone H3. A typical PHD finger binds to the unmodified or methylated amino-terminal tail of H3. This interaction is highly specific and can be regulated by post-translational modifications (PTMs) in H3 and other domains present in the protein. However, a set of PHD fingers has recently been shown to bind non-histone proteins, H3 mimetics, and DNA. In this review, we highlight the molecular mechanisms by which PHD fingers interact with ligands other than the amino terminus of H3 and discuss similarities and differences in engagement with histone and non-histone binding partners.


Assuntos
Proteínas de Ligação a DNA , Dedos de Zinco PHD , Proteínas de Ligação a DNA/metabolismo , Histonas/metabolismo , Plantas , Ligação Proteica
4.
Mol Cell ; 74(5): 862-863, 2019 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-31173720

RESUMO

Cryo-EM structures of Dot1L in complex with a ubiquitinated nucleosome provide the long-sought-after molecular mechanism of Dot1L-mediated methylation of lysine 79 in histone H3 and explain crosstalk with histone H2B ubiquitination.


Assuntos
Histonas , Nucleossomos , Lisina , Metilação , Metiltransferases/genética , Ubiquitinação
5.
Mol Cell ; 68(2): 261-262, 2017 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-29053953

RESUMO

Epigenetic marks, including DNA methylation and posttranslational modifications (PTMs) in histones, are important factors in determining the fate of replicating cells. In this issue of Molecular Cell, Ishiyama et al. (2017) reveal yet another layer in a remarkably complex mechanism of maintenance DNA methylation.


Assuntos
Metilação de DNA , Histonas/genética , Processamento de Proteína Pós-Traducional , Ubiquitina , Ubiquitinação
6.
J Biol Chem ; 299(4): 104601, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36907441

RESUMO

Plant homeodomain (PHD) fingers are structurally conserved zinc fingers that selectively bind unmodified or methylated at lysine 4 histone H3 tails. This binding stabilizes transcription factors and chromatin-modifying proteins at specific genomic sites, which is required for vital cellular processes, including gene expression and DNA repair. Several PHD fingers have recently been shown to recognize other regions of H3 or histone H4. In this review, we detail molecular mechanisms and structural features of the noncanonical histone recognition, discuss biological implications of the atypical interactions, highlight therapeutic potential of PHD fingers, and compare inhibition strategies.


Assuntos
Histonas , Dedos de Zinco PHD , Proteínas de Ligação a DNA/metabolismo , Histonas/química , Histonas/metabolismo , Ligação Proteica , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Camundongos , Neoplasias/genética , Neoplasias/fisiopatologia
7.
J Biol Chem ; 298(12): 102651, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36377105

RESUMO

Numerous studies have demonstrated antioxidant, anti-inflammatory, antimicrobial, anticancer, and cardio-protective activities of dietary polyphenols, but due to diverse structures and subclasses of polyphenols, little is known about their mechanisms of action. The study by Yamaguchi et al. published in JBC provides mechanistic insights into how dietary polyphenols confer histone-binding ability on certain proteins and motivates the research community to further explore health benefits of polyphenols.


Assuntos
Dieta , Histonas , Polifenóis , Histonas/metabolismo , Polifenóis/metabolismo
8.
Genes Dev ; 29(17): 1795-800, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26341557

RESUMO

The YEATS domain, found in a number of chromatin-associated proteins, has recently been shown to have the capacity to bind histone lysine acetylation. Here, we show that the YEATS domain of Taf14, a member of key transcriptional and chromatin-modifying complexes in yeast, is a selective reader of histone H3 Lys9 acetylation (H3K9ac). Structural analysis reveals that acetylated Lys9 is sandwiched in an aromatic cage formed by F62 and W81. Disruption of this binding in cells impairs gene transcription and the DNA damage response. Our findings establish a highly conserved acetyllysine reader function for the YEATS domain protein family and highlight the significance of this interaction for Taf14.


Assuntos
Reparo do DNA/genética , Regulação Fúngica da Expressão Gênica/genética , Histonas/metabolismo , Modelos Moleculares , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/genética , Fator de Transcrição TFIID/metabolismo , Acetilação , Dano ao DNA , Histonas/química , Histonas/genética , Ligação Proteica/genética , Estrutura Terciária de Proteína/genética , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/metabolismo
9.
Trends Biochem Sci ; 43(7): 487-489, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29731341

RESUMO

Polycomb repressive complex 2 (PRC2) is a chief epigenetic regulator. In a new article, Chen et al. describe the crystal structure of the heterotetrameric PRC2 holo complex, which provides important mechanistic insights into the organization of its subunits and the association of PRC2 with chromatin.


Assuntos
Cromatina , Complexo Repressor Polycomb 2/genética , Histonas/genética , Proteínas Repressoras/genética
10.
Biochem J ; 478(19): 3613-3619, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34624071

RESUMO

Methylation of lysine residues plays crucial roles in a wide variety of cell signaling processes. While the biological importance of recognition of methylated histones by reader domains in the cell nucleus is well established, the processes associated with methylation of non-histone proteins, particularly in the cytoplasm of the cell, are not well understood. Here, we describe a search for potential methyllysine readers using a rapid structural motif-mining algorithm Erebus, the PDB database, and knowledge of the methyllysine binding mechanisms.


Assuntos
Histonas/química , Histonas/metabolismo , Lisina/metabolismo , Domínios Proteicos , Algoritmos , Citosol/metabolismo , Bases de Dados de Proteínas , Epigênese Genética , Humanos , Metilação , Modelos Moleculares , Ligação Proteica , Processamento de Proteína Pós-Traducional
11.
Proc Natl Acad Sci U S A ; 116(13): 6111-6119, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30850548

RESUMO

Microrchidia 3 (MORC3) is a human protein linked to autoimmune disorders, Down syndrome, and cancer. It is a member of a newly identified family of human ATPases with an uncharacterized mechanism of action. Here, we elucidate the molecular basis for inhibition and activation of MORC3. The crystal structure of the MORC3 region encompassing the ATPase and CW domains in complex with a nonhydrolyzable ATP analog demonstrates that the two domains are directly coupled. The extensive ATPase:CW interface stabilizes the protein fold but inhibits the catalytic activity of MORC3. Enzymatic, NMR, mutational, and biochemical analyses show that in the autoinhibited, off state, the CW domain sterically impedes binding of the ATPase domain to DNA, which in turn is required for the catalytic activity. MORC3 autoinhibition is released by disrupting the intramolecular ATPase:CW coupling through the competitive interaction of CW with histone H3 tail or by mutating the interfacial residues. Binding of CW to H3 leads to a marked rearrangement in the ATPase-CW cassette, which frees the DNA-binding site in active MORC3 (on state). We show that ATP-induced dimerization of the ATPase domain is strictly required for the catalytic activity and that the dimeric form of ATPase-CW might cooperatively bind to dsDNA. Together, our findings uncovered a mechanism underlying the fine-tuned regulation of the catalytic domain of MORC3 by the epigenetic reader, CW.


Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Adenosina Trifosfatases/química , Adenosina Trifosfatases/isolamento & purificação , Catálise , Domínio Catalítico , Cristalografia por Raios X , DNA/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/isolamento & purificação , Ativação Enzimática , Polarização de Fluorescência , Histonas/metabolismo , Humanos , Espectroscopia de Ressonância Magnética
12.
Int J Mol Sci ; 23(12)2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35743155

RESUMO

B-cell chronic lymphocytic leukemia (CLL) results from intrinsic genetic defects and complex microenvironment stimuli that fuel CLL cell growth through an array of survival signaling pathways. Novel small-molecule agents targeting the B-cell receptor pathway and anti-apoptotic proteins alone or in combination have revolutionized the management of CLL, yet combination therapy carries significant toxicity and CLL remains incurable due to residual disease and relapse. Single-molecule inhibitors that can target multiple disease-driving factors are thus an attractive approach to combat both drug resistance and combination-therapy-related toxicities. We demonstrate that SRX3305, a novel small-molecule BTK/PI3K/BRD4 inhibitor that targets three distinctive facets of CLL biology, attenuates CLL cell proliferation and promotes apoptosis in a dose-dependent fashion. SRX3305 also inhibits the activation-induced proliferation of primary CLL cells in vitro and effectively blocks microenvironment-mediated survival signals, including stromal cell contact. Furthermore, SRX3305 blocks CLL cell migration toward CXCL-12 and CXCL-13, which are major chemokines involved in CLL cell homing and retention in microenvironment niches. Importantly, SRX3305 maintains its anti-tumor effects in ibrutinib-resistant CLL cells. Collectively, this study establishes the preclinical efficacy of SRX3305 in CLL, providing significant rationale for its development as a therapeutic agent for CLL and related disorders.


Assuntos
Leucemia Linfocítica Crônica de Células B , Proteínas de Ciclo Celular/farmacologia , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas Nucleares , Fosfatidilinositol 3-Quinases , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Antígenos de Linfócitos B/metabolismo , Fatores de Transcrição , Microambiente Tumoral
13.
Crit Rev Biochem Mol Biol ; 54(1): 1-10, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30691308

RESUMO

Although relatively small in size, the ZZ-type zinc finger (ZZ) domain is a versatile signaling module that is implicated in a diverse set of cell signaling events. Here, we highlight the most recent studies focused on the ZZ domain function as a histone reader and a sensor of protein degradation signals. We review and compare the molecular and structural mechanisms underlying targeting the amino-terminal sequences of histone H3 and arginylated substrates by the ZZ domain. We also discuss the ZZ domain sensitivity to histone PTMs and summarize biological outcomes associated with the recognition of histone and non-histone ligands by the ZZ domain-containing proteins and complexes.


Assuntos
Epigênese Genética , Dedos de Zinco , Acetilação , Animais , Autofagia , Cromatina/genética , Cromatina/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Processamento de Proteína Pós-Traducional
14.
J Mol Cell Cardiol ; 153: 44-59, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33359755

RESUMO

Direct reprogramming of fibroblasts into cardiomyocytes (CMs) represents a promising strategy to regenerate CMs lost after ischemic heart injury. Overexpression of GATA4, HAND2, MEF2C, TBX5, miR-1, and miR-133 (GHMT2m) along with transforming growth factor beta (TGF-ß) inhibition efficiently promote reprogramming. However, the mechanisms by which TGF-ß blockade promotes cardiac reprogramming remain unknown. Here, we identify interactions between the histone H3 lysine 27 trimethylation (H3K27me3) demethylase JMJD3, the SWI/SNF remodeling complex subunit BRG1, and cardiac transcription factors. Furthermore, canonical TGF-ß signaling regulates the interaction between GATA4 and JMJD3. TGF-ß activation impairs the ability of GATA4 to bind target genes and prevents demethylation of H3K27 at cardiac gene promoters during cardiac reprogramming. Finally, a mutation in GATA4 (V267M) that is associated with congenital heart disease exhibits reduced binding to JMJD3 and impairs cardiomyogenesis. Thus, we have identified an epigenetic mechanism wherein canonical TGF-ß pathway activation impairs cardiac gene programming, in part by interfering with GATA4-JMJD3 interactions.


Assuntos
Fator de Transcrição GATA4/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células-Tronco Pluripotentes Induzidas/citologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , Miócitos Cardíacos/citologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Animais , Metilação de DNA , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Fator de Transcrição GATA4/genética , Histonas/química , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Camundongos , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo
16.
Genes Dev ; 27(18): 2009-24, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-24065767

RESUMO

Histone acetyltransferases (HATs) assemble into multisubunit complexes in order to target distinct lysine residues on nucleosomal histones. Here, we characterize native HAT complexes assembled by the BRPF family of scaffold proteins. Their plant homeodomain (PHD)-Zn knuckle-PHD domain is essential for binding chromatin and is restricted to unmethylated H3K4, a specificity that is reversed by the associated ING subunit. Native BRPF1 complexes can contain either MOZ/MORF or HBO1 as catalytic acetyltransferase subunit. Interestingly, while the previously reported HBO1 complexes containing JADE scaffold proteins target histone H4, the HBO1-BRPF1 complex acetylates only H3 in chromatin. We mapped a small region to the N terminus of scaffold proteins responsible for histone tail selection on chromatin. Thus, alternate choice of subunits associated with HBO1 can switch its specificity between H4 and H3 tails. These results uncover a crucial new role for associated proteins within HAT complexes, previously thought to be intrinsic to the catalytic subunit.


Assuntos
Histona Acetiltransferases/metabolismo , Histonas/metabolismo , Acetilação , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sequência de Aminoácidos , Cromatina/metabolismo , Proteínas de Ligação a DNA , Células HEK293 , Células HeLa , Histona Acetiltransferases/química , Histona Acetiltransferases/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Metilação , Dados de Sequência Molecular , Proteínas Nucleares/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Alinhamento de Sequência , Especificidade por Substrato , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/metabolismo
17.
Biochemistry ; 59(4): 389-399, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31746185

RESUMO

Transcription factor 19 (TCF19) plays critical roles in type 1 diabetes and the maintenance of pancreatic ß cells. Recent studies have also implicated TCF19 in cell proliferation of hepatic carcinoma and non-small cell lung carcinoma; however, the mechanism underlying this regulation remains elusive. At the molecular level, TCF19 contains two modules, the plant homeodomain (PHD) finger and the forkhead-associated (FHA) domain, of unclear function. Here, we show that TCF19 mediates hepatocellular carcinoma HepG2 cell proliferation through its PHD finger that recognizes trimethylated lysine 4 of histone 3 (H3K4me3). W316 of the PHD finger of TCF19 is one of the critical residues eliciting this function. Whole genome microarray analysis and orthogonal cell-based assays identified a large subset of genes involved in cell survival and proliferation that depend on TCF19. Our data suggest that TCF19 acts as a pro-oncogene in hepatocellular carcinoma cells and that its functional PHD finger is critical in cell proliferation.


Assuntos
Histonas/metabolismo , Fatores de Transcrição/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Proteínas de Ligação a DNA/metabolismo , Células Hep G2 , Código das Histonas , Histonas/genética , Humanos , Neoplasias Hepáticas/metabolismo , Lisina/metabolismo , Metilação , Modelos Moleculares , Dedos de Zinco PHD/fisiologia , Ligação Proteica , Fatores de Transcrição/fisiologia
18.
Biochem J ; 476(16): 2351-2354, 2019 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-31462441

RESUMO

Binding of the Spp1 PHD finger to histone H3K4me3 is sensitive to adjacent post-translational modifications in the histone tail. This commentary discusses the findings of He and colleagues [Biochem. J.476, 1957-1973] which show that the PHD finger binds to H3K4me3 in a selective manner which is conserved in the Saccharomyces pombe and mammalian orthologues of Spp1.


Assuntos
Histonas , Dedos de Zinco PHD , Animais , Código das Histonas , Modelos Moleculares , Ligação Proteica , Processamento de Proteína Pós-Traducional
19.
Nucleic Acids Res ; 46(1): 421-430, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29145630

RESUMO

Yaf9 is an integral part of the NuA4 acetyltransferase and the SWR1 chromatin remodeling complexes. Here, we show that Yaf9 associates with acetylated histone H3 with high preference for H3K27ac. The crystal structure of the Yaf9 YEATS domain bound to the H3K27ac peptide reveals that the sequence C-terminal to K27ac stabilizes the complex. The side chain of K27ac inserts between two aromatic residues, mutation of which abrogates the interaction in vitro and leads in vivo to phenotypes similar to YAF9 deletion, including loss of SWR1-dependent incorporation of variant histone H2A.Z. Our findings reveal the molecular basis for the recognition of H3K27ac by a YEATS reader and underscore the importance of this interaction in mediating Yaf9 function within the NuA4 and SWR1 complexes.


Assuntos
Adenosina Trifosfatases/metabolismo , Histona Acetiltransferases/metabolismo , Histonas/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Acetilação , Adenosina Trifosfatases/química , Adenosina Trifosfatases/genética , Sequência de Aminoácidos , Sítios de Ligação/genética , Histona Acetiltransferases/química , Histona Acetiltransferases/genética , Histonas/química , Complexos Multiproteicos/química , Complexos Multiproteicos/genética , Domínios Proteicos , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Homologia de Sequência de Aminoácidos
20.
Proc Natl Acad Sci U S A ; 114(7): E1072-E1080, 2017 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-28137841

RESUMO

MYC is a major cancer driver but is documented to be a difficult therapeutic target itself. Here, we report on the biological activity, the structural basis, and therapeutic effects of the family of multitargeted compounds that simultaneously disrupt functions of two critical MYC-mediating factors through inhibiting the acetyllysine binding of BRD4 and the kinase activity of PI3K. We show that the dual-action inhibitor impairs PI3K/BRD4 signaling in vitro and in vivo and affords maximal MYC down-regulation. The concomitant inhibition of PI3K and BRD4 blocks MYC expression and activation, promotes MYC degradation, and markedly inhibits cancer cell growth and metastasis. Collectively, our findings suggest that the dual-activity inhibitor represents a highly promising lead compound for the development of novel anticancer therapeutics.


Assuntos
Antineoplásicos/farmacologia , Morfolinas/farmacologia , Metástase Neoplásica/prevenção & controle , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Nucleares/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Piranos/farmacologia , Tiofenos/farmacologia , Fatores de Transcrição/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/enzimologia , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/secundário , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Morfolinas/uso terapêutico , Metástase Neoplásica/tratamento farmacológico , Proteínas de Neoplasias/fisiologia , Neuroblastoma/tratamento farmacológico , Neuroblastoma/enzimologia , Neuroblastoma/patologia , Neuroblastoma/secundário , Proteínas Nucleares/química , Proteínas Nucleares/fisiologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/patologia , Conformação Proteica , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-myc/fisiologia , Piranos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Tiofenos/uso terapêutico , Fatores de Transcrição/química , Fatores de Transcrição/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto
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