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1.
Nucleic Acids Res ; 52(6): 3310-3326, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38165001

RESUMO

L1TD1 is a cytoplasmic RNA-binding protein specifically expressed in pluripotent stem cells and, unlike its mouse ortholog, is essential for the maintenance of stemness in human cells. Although L1TD1 is the only known protein-coding gene domesticated from a LINE-1 (L1) retroelement, the functional legacy of its ancestral protein, ORF1p of L1, and how it is manifested in L1TD1 are still unknown. Here, we determined RNAs associated with L1TD1 and found that, like ORF1p, L1TD1 binds L1 RNAs and localizes to high-density ribonucleoprotein (RNP) condensates. Unexpectedly, L1TD1 enhanced the translation of a subset of mRNAs enriched in the condensates. L1TD1 depletion promoted the formation of stress granules in embryonic stem cells. In HeLa cells, ectopically expressed L1TD1 facilitated the dissolution of stress granules and granules formed by pathological mutations of TDP-43 and FUS. The glutamate-rich domain and the ORF1-homology domain of L1TD1 facilitated dispersal of the RNPs and induced autophagy, respectively. These results provide insights into how L1TD1 regulates gene expression in pluripotent stem cells. We propose that the ability of L1TD1 to dissolve stress granules may provide novel opportunities for treatment of neurodegenerative diseases caused by disturbed stress granule dynamics.


Assuntos
Células-Tronco Embrionárias , Proteínas de Ligação a RNA , Ribonucleoproteínas , Animais , Humanos , Camundongos , Grânulos Citoplasmáticos/metabolismo , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Células HeLa , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , RNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
2.
Nucleic Acids Res ; 52(3): 1420-1434, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38088204

RESUMO

Recurring mutations in genes encoding 3' splice-site recognition proteins, U2AF1 and ZRSR2 are associated with human cancers. Here, we determined binding sites of the proteins to reveal that U2-type and U12-type splice sites are recognized by U2AF1 and ZRSR2, respectively. However, some sites are spliced by both the U2-type and U12-type spliceosomes, indicating that well-conserved consensus motifs in some U12-type introns could be recognized by the U2-type spliceosome. Nucleotides flanking splice sites of U12-type introns are different from those flanking U2-type introns. Remarkably, the AG dinucleotide at the positions -1 and -2 of 5' splice sites of U12-type introns with GT-AG termini is not present. AG next to 5' splice site introduced by a single nucleotide substitution at the -2 position could convert a U12-type splice site to a U2-type site. The class switch of introns by a single mutation and the bias against G at the -1 position of U12-type 5' splice site support the notion that the identities of nucleotides in exonic regions adjacent to splice sites are fine-tuned to avoid recognition by the U2-type spliceosome. These findings may shed light on the mechanism of selectivity in U12-type intron splicing and the mutations that affect splicing.


Assuntos
Sítios de Splice de RNA , Ribonucleoproteínas , Spliceossomos , Fator de Processamento U2AF , Humanos , Sítios de Ligação , Íntrons , Nucleotídeos/metabolismo , Ribonucleoproteínas/metabolismo , Splicing de RNA , RNA Nuclear Pequeno/genética , RNA Nuclear Pequeno/metabolismo , Proteínas de Ligação a RNA/metabolismo , Spliceossomos/genética , Spliceossomos/metabolismo , Fator de Processamento U2AF/genética , Fator de Processamento U2AF/metabolismo
3.
Mol Oncol ; 13(5): 1280-1295, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30927556

RESUMO

The epithelial-mesenchymal transition (EMT) plays a pivotal role in the conversion of early-stage tumors into invasive malignancies. The transcription factor Snail, an extremely unstable protein whose subcellular levels are regulated by many E3 ubiquitin ligases, promotes EMT as well as associated pathological characteristics including migration, invasion, and metastasis. Through yeast two-hybrid screening, we identified the carboxyl terminus of Hsc70-interacting protein (CHIP) as a novel Snail ubiquitin ligase that interacts with Snail to induce ubiquitin-mediated proteasomal degradation. Inhibition of CHIP expression increases Snail protein levels, induces EMT, and enhances in vitro migration and invasion as well as in vivo metastasis of ovarian cancer cells. In turn, Snail depletion abrogates all phenomena induced by CHIP depletion. Finally, Snail and CHIP expression is inversely correlated in ovarian tumor tissues. These findings establish the CHIP-Snail axis as a post-translational mechanism of EMT and cancer metastasis regulation.


Assuntos
Regulação para Baixo , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/metabolismo , Neoplasias Ovarianas/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Ubiquitina-Proteína Ligases/biossíntese , Animais , Feminino , Células HCT116 , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Metástase Neoplásica , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fatores de Transcrição da Família Snail/genética , Ubiquitina-Proteína Ligases/genética
4.
Sci Rep ; 8(1): 14581, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30275449

RESUMO

Bone morphogenetic protein 2 (BMP-2) is considered an effective growth factor for bone formation, and is used for making osteo-inductive scaffolds, but the related clinical investigations have shown low success rates. In this study, we genetically manipulated teratoma-derived fibroblast (TDF) cells by simultaneous introduction of BMP-2 and herpes simplex virus-thymidine kinase (HSV-tk) encoding genes. Self-production of BMP-2 in TDF cells strongly enhanced the alkaline phosphatase (ALP) activity, calcium content, and elevated the mRNA expression of osteogenic marker genes during in vitro osteogenesis. The bone formation volume was also remarkably enhanced in calvarial and femoral critical-size defect models. Ganciclovir (GCV) treatment induced apoptosis in TDF cells co-expressing HSV-tk and BMP-2, implying that HSV-tk suicide gene can modulate the side-effects of stem cell therapy, e.g., development of uncontrollable teratoma and tumor formation. Altogether, our findings revealed a safe and highly efficient technique with potential therapeutic applications for bone regeneration.


Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Fibroblastos/metabolismo , Fibroblastos/fisiologia , Osteogênese , Proteínas Recombinantes/metabolismo , Animais , Doenças Ósseas/terapia , Proteína Morfogenética Óssea 2/genética , Linhagem Celular , Modelos Animais de Doenças , Expressão Gênica , Humanos , Camundongos Endogâmicos BALB C , Ratos Sprague-Dawley , Proteínas Recombinantes/genética , Crânio/patologia , Timidina Quinase/genética , Timidina Quinase/metabolismo , Tíbia/patologia , Resultado do Tratamento
5.
Biochim Biophys Acta Gene Regul Mech ; 1861(7): 603-612, 2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29935344

RESUMO

MicroRNAs (miRNAs) of the miR-17-92 cluster are overexpressed in human cancers, and their enforced expression is tumorigenic in mouse models. A number of genes are reported to be targets of these miRNAs and are implicated in their tumorigenic potential. However, the mode of action by miRNAs suggests that global analysis of their targets is required to understand their cellular roles. In this study, we globally analyzed AGO2-bound mRNAs and found that the miR-17-92 miRNAs coherently repress multiple targets involved in the destabilization of mRNA. While the miRNAs repress the expression of their targets, they increase stability and lengthen the poly-A tails of non-target mRNAs. Furthermore, the expression of BTG3, TOB1, CSNK1A1 and ANKRD52 is negatively correlated with the expression of the miR-17-92 cluster in cancer cell lines. Our results suggest that the miR-17-92 miRNAs promote tumorigenesis not only by repression of key regulators, but also by posttranscriptional increases of global gene expression.

6.
Biochim Biophys Acta Gene Regul Mech ; 1860(11): 1148-1158, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29031931

RESUMO

Among the four Argonaute family members in mammals, only AGO2 protein retains endonuclease activity and facilitates cleavage of target RNAs base-pairing with highly complementary guide RNAs. Despite the deeply conserved catalytic activity, only a small number of targets have been reported to extensively base pair with cognate miRNAs to be cleaved by AGO2. Here, we analyzed AGO2-bound RNAs by CrossLinking ImmunoPrecipitation (CLIP) of genetically modified cells that express epitope-tagged AGO2 from the native genomic locus. We found that HMGA2 mRNA is cleaved by AGO2 loaded with let-7 and miR-21. In contrast to the generally accepted notion, the base-pairing from the seed region to the cleavage site, rather than perfect or near perfect complementarity, was required for cleavage of the target mRNA in cells. Non-templated addition of nucleotides at the 3' end of the cleaved RNA was observed, further supporting the AGO2-mediated cleavage. Based on the observation that the limited complementarity is the minimum requirement for cleavage, we found that AGO2-mediated cleavage of targets is more common than previously thought. Our result may explain the vital role of endonuclease activity in controlling miRNA-mediated gene regulation.


Assuntos
Proteínas Argonautas/metabolismo , Pareamento de Bases/fisiologia , MicroRNAs/metabolismo , Clivagem do RNA , RNA Mensageiro/metabolismo , Animais , Células Cultivadas , Regulação da Expressão Gênica , Células HeLa , Humanos , Camundongos , Camundongos SCID , MicroRNAs/genética , Ligação Proteica , RNA Mensageiro/genética
7.
Nucleic Acids Res ; 42(20): 12806-21, 2014 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-25326327

RESUMO

The Microprocessor plays an essential role in canonical miRNA biogenesis by facilitating cleavage of stem-loop structures in primary transcripts to yield pre-miRNAs. Although miRNA biogenesis has been extensively studied through biochemical and molecular genetic approaches, it has yet to be addressed to what extent the current miRNA biogenesis models hold true in intact cells. To address the issues of in vivo recognition and cleavage by the Microprocessor, we investigate RNAs that are associated with DGCR8 and Drosha by using immunoprecipitation coupled with next-generation sequencing. Here, we present global protein-RNA interactions with unprecedented sensitivity and specificity. Our data indicate that precursors of canonical miRNAs and miRNA-like hairpins are the major substrates of the Microprocessor. As a result of specific enrichment of nascent cleavage products, we are able to pinpoint the Microprocessor-mediated cleavage sites per se at single-nucleotide resolution. Unexpectedly, a 2-nt 3' overhang invariably exists at the ends of cleaved bases instead of nascent pre-miRNAs. Besides canonical miRNA precursors, we find that two novel miRNA-like structures embedded in mRNAs are cleaved to yield pre-miRNA-like hairpins, uncoupled from miRNA maturation. Our data provide a framework for in vivo Microprocessor-mediated cleavage and a foundation for experimental and computational studies on miRNA biogenesis in living cells.


Assuntos
Proteínas Argonautas/metabolismo , Células-Tronco Embrionárias/enzimologia , MicroRNAs/metabolismo , Precursores de RNA/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ribonuclease III/metabolismo , Células Cultivadas , Células-Tronco Embrionárias/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunoprecipitação , MicroRNAs/química , Clivagem do RNA , Precursores de RNA/química , RNA Mensageiro/metabolismo , Análise de Sequência de RNA
8.
Biochem Biophys Res Commun ; 446(1): 241-7, 2014 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-24589731

RESUMO

Aurora kinase B regulates the segregation of chromosomes and the spindle checkpoint during mitosis. In this study, we showed that the Microprocessor complex, which is responsible for the processing of the primary transcripts during the generation of microRNAs, destabilizes the mRNA of Aurora kinase B in human cells. The Microprocessor-mediated cleavage kept Aurora kinase B at a low level and prevented premature entrance into mitosis. The cleavage was reduced during mitosis leading to the accumulation of Aurora kinase B mRNA and protein. In addition to Aurora kinase B mRNA, the processing of other primary transcripts of miRNAs were also decreased during mitosis. We found that the cleavage was dependent on an RNA helicase, DDX5, and the association of DDX5 and DDX17 with the Microprocessor was reduced during mitosis. Thus, we propose a novel mechanism by which the Microprocessor complex regulates stability of Aurora kinase B mRNA and cell cycle progression.


Assuntos
Aurora Quinase B/genética , Pontos de Checagem do Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular/fisiologia , Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ribonuclease III/metabolismo , Animais , Sequência de Bases , Células Cultivadas , RNA Helicases DEAD-box/antagonistas & inibidores , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Camundongos , Modelos Biológicos , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Mutação , Conformação de Ácido Nucleico , Proteínas/antagonistas & inibidores , Proteínas/genética , Estabilidade de RNA , RNA Mensageiro/química , Proteínas de Ligação a RNA , Ribonuclease III/genética
9.
Rev Sci Instrum ; 82(7): 074301, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21806202

RESUMO

Force feedback plays a very important role in medical surgery. In minimally invasive surgery (MIS), however, the very long and stiff bars of surgical instruments greatly diminish force feedback for the surgeon. In the case of minimally invasive robotic surgery (MIRS), force feedback is totally eliminated. Previous researchers have reported that the absence of force feedback increased the average force magnitude applied to the tissue by at least 50%, and increased the peak force magnitude by at least a factor of two. Therefore, it is very important to provide force information in MIRS. Recently, many sensors are being developed for MIS and MIRS, but some obstacles to their application in actual medical surgery must be surmounted. The most critical problems are size limit and sterilizability. Optical fiber sensors are among the most suitable sensors for the surgical environment. The optical fiber Bragg grating (FBG) sensor, in particular, offers an important additional advantage over other optical fiber sensors in that it is not influenced by the intensity of the light source. In this paper, we present the initial results of a study on the application of a FBG sensor to measure reflected forces in MIRS environments and suggest the possibility of successful application to MIRS systems.


Assuntos
Procedimentos Cirúrgicos Minimamente Invasivos/instrumentação , Fibras Ópticas , Robótica/instrumentação , Segurança , Fenômenos Mecânicos , Instrumentos Cirúrgicos , Fatores de Tempo
10.
Discov Med ; 9(49): 500-3, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20587338

RESUMO

Mouse models have become an indispensable tool to study the pathogenesis of human diseases. However, due to the apparent cellular and physiological differences between mouse and human, mouse models often fail to faithfully recapitulate certain defects observed in human patients. In addition, these differences contribute to the dilemma in drug development that many therapeutic strategies work well in mouse models but do poorly in human patients. Therefore, it has become increasingly important to develop additional physiologically relevant human disease models for mechanistic studies and drug development. With the unlimited self-renewal capability and the pluripotency to differentiate into all cell types in the body, human embryonic stem cells (hESCs) with causative genetic mutations as well as their differentiated derivatives represent the much needed human disease models for studies on disease mechanisms and for drug development. Here we summarize recent progresses in developing hESCs into human disease models.


Assuntos
Pesquisa Biomédica , Desenho de Fármacos , Células-Tronco Embrionárias , Engenharia Genética , Animais , Cromossomos Artificiais Bacterianos , Marcação de Genes , Humanos , Camundongos , Recombinação Genética
11.
Cell Stem Cell ; 6(1): 80-9, 2010 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-20074536

RESUMO

Although mouse models have been valuable for studying human disease, the cellular and physiological differences between mouse and human have made it increasingly important to develop more relevant human disease models for mechanistic studies and drug discovery. Human embryonic stem cells (hESCs), which can undergo unlimited self-renewal and retain the potential to differentiate into all cell types, present a possible solution. To improve the efficiency of genetic manipulation of hESCs, we have developed bacterial artificial chromosome (BAC) based approach that enables high efficiency homologous recombination. By sequentially disrupting both alleles of ATM or p53 with BAC targeting vectors, we have established ATM(-/-) and p53(-/-) hESCs as models for two major human genetic instability syndromes and used the generated cells to reveal the importance of p53 in maintaining genome stability of hESCs. Our findings suggest that it will be feasible to develop genetically modified hESCs as relevant human disease models.


Assuntos
Cromossomos Bacterianos/genética , Células-Tronco Embrionárias/metabolismo , Recombinação Genética , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular/efeitos da radiação , Células Cultivadas , Dano ao DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Embrionárias/citologia , Vetores Genéticos , Instabilidade Genômica , Humanos , Masculino , Camundongos , Camundongos SCID , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
12.
Cell Cycle ; 6(13): 1570-3, 2007 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-17598983

RESUMO

Loss of the tumor suppression activity of p53 is required for the progression of most human cancers. In this context, p53 gene is somatically mutated in about half of all human cancers; in the rest human cancers, p53 is mostly inactivated due to the disruption of pathways important for its activation. Most p53 cancer mutations are missense mutations within the core domain, leading to the expression of full-length mutant p53 protein. The expression of p53 mutants is usually correlated with the poor prognosis of the cancer patients. Accumulating evidence has indicated that p53 cancer mutants not only lose the tumor suppression activity of WT p53, but also gain novel oncogenic activities to promote tumorigenesis and drug resistance. Therefore, to improve current cancer therapy, it is critical to elucidate the gain-of-functions of p53 cancer mutants. By analyzing the humanized p53 mutant knock-in mouse models, we have identified a new gain of function of the common p53 cancer mutants in inducing genetic instability by disrupting ATM-mediated cellular responses to DNA double-stranded break (DSB) damage. Considering that some current cancer therapies such as radiotherapy kills the cancer cells by inducing DSBs in their genome DNA, our findings will have important implications on the treatment of human cancers that express common p53 mutants.


Assuntos
Dano ao DNA/genética , Proteínas Mutantes/fisiologia , Neoplasias/genética , Proteína Supressora de Tumor p53/fisiologia , Animais , Humanos , Modelos Biológicos , Mutação , Proteína Supressora de Tumor p53/genética
13.
Nat Cell Biol ; 9(5): 573-80, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17417627

RESUMO

Tp53 is the most commonly mutated tumour-suppressor gene in human cancers. In addition to the loss of tumour-suppression function, some missense mutants gain novel oncogenic activities. To elucidate the nature of the gain of function, we introduced the most common p53 cancer mutations (R248W and R273H) independently into the humanized p53 knock-in (HUPKI) allele in mice. Tumour-suppressor functions of p53 are abolished in p53-mutant mice. Several lines of evidence further indicate gain-of-function of p53 mutants in promoting tumorigenesis. p53(R248W) mice rapidly succumb to certain types of cancers not commonly observed in p53(-/-) mice. Interchromosomal translocations, a type of genetic instability rarely observed in p53(-/-) cells, are readily detectable in p53-mutant pre-tumor thymocytes. Although normal in p53(-/-) mouse cells, the G(2)-M checkpoint is impaired in p53-mutant cells after DNA damage. These acquired oncogenic properties of mutant p53 could be explained by the findings that these p53 mutants interact with the nuclease Mre11 and suppress the binding of the Mre11-Rad50-NBS1 (MRN) complex to DNA double-stranded breaks (DSBs), leading to impaired Ataxia-telangiectasia mutated (ATM) activation. Therefore, p53 gain-of-function mutants promote tumorigenesis by a novel mechanism involving active disruption of critical DNA damage-response pathways.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Transformação Celular Neoplásica/genética , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Instabilidade Genômica , Mutação , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais/genética , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Hidrolases Anidrido Ácido , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Ciclo Celular/genética , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Enzimas Reparadoras do DNA/metabolismo , Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Histonas/metabolismo , Humanos , Proteína Homóloga a MRE11 , Camundongos , Camundongos Transgênicos , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Timo/citologia , Timo/metabolismo , Transcrição Gênica , Translocação Genética , Proteína Supressora de Tumor p53/metabolismo , Raios Ultravioleta
14.
Mol Cell Biol ; 25(2): 661-70, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15632067

RESUMO

Ataxia-telangiectasia (A-T) mutated (ATM) kinase signals all three cell cycle checkpoints after DNA double-stranded break (DSB) damage. H2AX, NBS1, and p53 are substrates of ATM kinase and are involved in ATM-dependent DNA damage responses. We show here that H2AX is dispensable for the activation of ATM and p53 responses after DNA DSB damage. Therefore, H2AX functions primarily as a downstream mediator of ATM functions in the parallel pathway of p53. NBS1 appears to function both as an activator of ATM and as an adapter to mediate ATM activities after DNA DSB damage. Phosphorylation of ATM and H2AX induced by DNA DSB damage is normal in NBS1 mutant/mutant (NBS1m/m) mice that express an N-terminally truncated NBS1 at lower levels. Therefore, the pleiotropic A-T-related systemic and cellular defects observed in NBS1m/m mice are due to the disruption of the adapter function of NBS1 in mediating ATM activities. While H2AX is required for the irradiation-induced focus formation of NBS1, our findings indicate that NBS1 and H2AX have distinct roles in DNA damage responses. ATM-dependent phosphorylation of p53 and p53 responses are largely normal in NBS1m/m mice after DNA DSB damage, and p53 deficiency greatly facilitates tumorigenesis in NBS1m/m mice. Therefore, NBS1, H2AX, and p53 play synergistic roles in ATM-dependent DNA damage responses and tumor suppression.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Ciclo Celular/fisiologia , Dano ao DNA , Proteínas de Ligação a DNA/metabolismo , Histonas/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/genética , Células Cultivadas , Quinase do Ponto de Checagem 2 , Proteínas de Ligação a DNA/genética , Fibroblastos/citologia , Fibroblastos/fisiologia , Fibroblastos/efeitos da radiação , Genes Supressores de Tumor , Histonas/genética , Humanos , Cariotipagem , Linfoma/genética , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Radiação Ionizante , Serina/metabolismo , Transcrição Gênica , Translocação Genética , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética
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