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1.
Int J Occup Med Environ Health ; 36(5): 575-586, 2023 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-37767779

RESUMO

Bisphenols, endocrine disrupting chemicals, are widely used in daily life. Continued exposure during key developmental periods of life (pregnancy, infancy and early childhood) can contribute to adverse health consequences such as decreased lung function, wheezing/asthma, the occurrence of allergies or changes in immune system responses. The purpose of this review is to present the current state of knowledge on the effects of prenatal or postnatal exposure to bisphenol A (BPA), bisphenol S (BPS) and bisphenol F (BPF) on the development of allergic diseases in childhood. A com- prehensive and systematic search of PubMed, Scopus and Web of Science databases was conducted. The review is restricted to studies published since 2015, in English in peer-reviewed journals. Based on keywords, 2648 studies were identified and reviewed for eligibility. Finally, 8 epidemio- logical studies were found to be appropriate for inclusion in this publication. The data collected in this review suggests that there is an associa- tion between maternal exposure during pregnancy or childhood to BPA and the development of allergic diseases. Most studies reported positive relationships between BPA exposure and at least one of the types of allergic disease. The paucity of studies and the observed differences in findings regarding the association between prenatal/postnatal exposure to BPS and/or BPF do not allow firm conclusions to be drawn. Further research is needed to identify the vulnerable population and the mechanisms responsible for the development of undesirable health consequences. Int J Occup Med Environ Health. 2023;36(5):575-86.


Assuntos
Asma , Exposição Materna , Pré-Escolar , Gravidez , Feminino , Humanos , Exposição Materna/efeitos adversos , Fenóis/toxicidade , Compostos Benzidrílicos/toxicidade , Asma/induzido quimicamente , Asma/epidemiologia
2.
Cancer Discov ; 3(2): 182-97, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23306062

RESUMO

UNLABELLED: Senescence induction contributes to cancer therapy responses and is crucial for p53-mediated tumor suppression. However, whether p53 inactivation actively suppresses senescence induction has been unclear. Here, we show that E2F1 overexpression, due to p53 or p21 inactivation, promotes expression of human oncoprotein CIP2A, which in turn, by inhibiting PP2A activity, increases stabilizing serine 364 phosphorylation of E2F1. Several lines of evidence show that increased activity of E2F1-CIP2A feedback renders breast cancer cells resistant to senescence induction. Importantly, mammary tumorigenesis is impaired in a CIP2A-deficient mouse model, and CIP2A-deficient tumors display markers of senescence induction. Moreover, high CIP2A expression predicts for poor prognosis in a subgroup of patients with breast cancer treated with senescence-inducing chemotherapy. Together, these results implicate the E2F1-CIP2A feedback loop as a key determinant of breast cancer cell sensitivity to senescence induction. This feedback loop also constitutes a promising prosenescence target for therapy of cancers with an inactivated p53-p21 pathway. SIGNIFICANCE: It has been recently realized that most currently used chemotherapies exert their therapeutic effect at least partly by induction of terminal cell arrest, senescence. However, the mechanisms by which cell-intrinsic senescence sensitivity is determined are poorly understood. Results of this study identify the E2F1-CIP2A positive feedback loop as a key determinant of breast cancer cell sensitivity to senescence and growth arrest induction. Our data also indicate that this newly characterized interplay between 2 frequently overexpressed oncoproteins constitutes a promising prosenescence target for therapy of cancers with inactivated p53 and p21. Finally, these results may also facilitate novel stratification strategies for selection of patients to receive senescence-inducing cancer therapies.


Assuntos
Autoantígenos/genética , Neoplasias da Mama/genética , Senescência Celular , Fator de Transcrição E2F1/genética , Retroalimentação Fisiológica , Proteínas de Membrana/genética , Animais , Antinematódeos/farmacologia , Autoantígenos/metabolismo , Western Blotting , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Docetaxel , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Fator de Transcrição E2F1/metabolismo , Embrião de Mamíferos/citologia , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Células HCT116 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Células MCF-7 , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/patologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxoides/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Vimblastina/análogos & derivados , Vimblastina/farmacologia , Vinorelbina
3.
Nat Med ; 18(8): 1239-47, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22820643

RESUMO

The inactivation of the p53 tumor suppressor pathway, which often occurs through mutations in TP53 (encoding tumor protein 53) is a common step in human cancer. However, in melanoma-a highly chemotherapy-resistant disease-TP53 mutations are rare, raising the possibility that this cancer uses alternative ways to overcome p53-mediated tumor suppression. Here we show that Mdm4 p53 binding protein homolog (MDM4), a negative regulator of p53, is upregulated in a substantial proportion (∼65%) of stage I-IV human melanomas and that melanocyte-specific Mdm4 overexpression enhanced tumorigenesis in a mouse model of melanoma induced by the oncogene Nras. MDM4 promotes the survival of human metastatic melanoma by antagonizing p53 proapoptotic function. Notably, inhibition of the MDM4-p53 interaction restored p53 function in melanoma cells, resulting in increased sensitivity to cytotoxic chemotherapy and to inhibitors of the BRAF (V600E) oncogene. Our results identify MDM4 as a key determinant of impaired p53 function in human melanoma and designate MDM4 as a promising target for antimelanoma combination therapy.


Assuntos
Melanoma/química , Proteínas de Neoplasias/fisiologia , Proteínas Nucleares/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Neoplasias Cutâneas/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas de Ciclo Celular , Linhagem Celular Tumoral/metabolismo , Linhagem Celular Tumoral/transplante , Peptídeos Penetradores de Células/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , GTP Fosfo-Hidrolases/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Queratinócitos/metabolismo , Masculino , Melanócitos/metabolismo , Melanoma/patologia , Melanoma/secundário , Melanoma Experimental/etiologia , Melanoma Experimental/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Camundongos Transgênicos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/biossíntese , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/biossíntese , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Recombinantes de Fusão/fisiologia , Transdução de Sinais/fisiologia , Ensaio Tumoral de Célula-Tronco , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/fisiologia , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Clin Invest ; 121(4): 1329-43, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21403399

RESUMO

Biochemical studies have suggested conflicting roles for the E3 ubiquitin ligase constitutive photomorphogenesis protein 1 (Cop1; also known as Rfwd2) in tumorigenesis, providing evidence for both the oncoprotein c-Jun and the tumor suppressor p53 as its targets. Here we present what we believe to be the first in vivo investigation of the role of Cop1 in cancer etiology. Using an innovative genetic approach to generate an allelic series of Cop1, we found that Cop1 hypomorphic mice spontaneously developed malignancy at a high frequency in the first year of life and were highly susceptible to radiation-induced lymphomagenesis. Further analysis revealed that c-Jun was a key physiological target for Cop1 and that Cop1 constitutively kept c-Jun at low levels in vivo and thereby modulated c-Jun/AP-1 transcriptional activity. Importantly, Cop1 deficiency stimulated cell proliferation in a c-Jun-dependent manner. Focal deletions of COP1 were observed at significant frequency across several cancer types, and COP1 loss was determined to be one of the mechanisms leading to c-Jun upregulation in human cancer. We therefore conclude that Cop1 is a tumor suppressor that functions, at least in part, by antagonizing c-Jun oncogenic activity. In the absence of evidence for a genetic interaction between Cop1 and p53, our data strongly argue against the use of Cop1-inhibitory drugs for cancer therapy.


Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Animais , Sequência de Bases , Proliferação de Células , Feminino , Heterozigoto , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Neoplasias/etiologia , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Nucleares/deficiência , Gravidez , Estabilidade Proteica , RNA Interferente Pequeno/genética , Fator de Transcrição AP-1/genética , Fator de Transcrição AP-1/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/deficiência , Ubiquitina-Proteína Ligases/deficiência
5.
Nat Chem Biol ; 7(5): 285-95, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21445056

RESUMO

Many p53 missense mutations possess dominant-negative activity and oncogenic gain of function. We report that for structurally destabilized p53 mutants, these effects result from mutant-induced coaggregation of wild-type p53 and its paralogs p63 and p73, thereby also inducing a heat-shock response. Aggregation of mutant p53 resulted from self-assembly of a conserved aggregation-nucleating sequence within the hydrophobic core of the DNA-binding domain, which becomes exposed after mutation. Suppressing the aggregation propensity of this sequence by mutagenesis abrogated gain of function and restored activity of wild-type p53 and its paralogs. In the p53 germline mutation database, tumors carrying aggregation-prone p53 mutations have a significantly lower frequency of wild-type allele loss as compared to tumors harboring nonaggregating mutations, suggesting a difference in clonal selection of aggregating mutants. Overall, our study reveals a novel disease mechanism for mutant p53 gain of function and suggests that, at least in some respects, cancer could be considered an aggregation-associated disease.


Assuntos
Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Animais , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Genes p53 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Mutação , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Conformação Proteica , Espectrometria de Massas por Ionização por Electrospray , Espectroscopia de Infravermelho com Transformada de Fourier , Transativadores/química , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição , Células Tumorais Cultivadas , Proteína Tumoral p73 , Proteína Supressora de Tumor p53/química , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
6.
EMBO J ; 29(15): 2538-52, 2010 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-20588255

RESUMO

MDM2 is a key regulator of the p53 tumor suppressor acting primarily as an E3 ubiquitin ligase to promote its degradation. MDM2 also inhibits p53 transcriptional activity by recruiting histone deacetylase and corepressors to p53. Here, we show that immunopurified MDM2 complexes have significant histone H3-K9 methyltransferase activity. The histone methyltransferases SUV39H1 and EHMT1 bind specifically to MDM2 but not to its homolog MDMX. MDM2 mediates formation of p53-SUV39H1/EHMT1 complex capable of methylating H3-K9 in vitro and on p53 target promoters in vivo. Furthermore, MDM2 promotes EHMT1-mediated p53 methylation at K373. Knockdown of SUV39H1 and EHMT1 increases p53 activity during stress response without affecting p53 levels, whereas their overexpression inhibits p53 in an MDM2-dependent manner. The p53 activator ARF inhibits SUV39H1 and EHMT1 binding to MDM2 and reduces MDM2-associated methyltransferase activity. These results suggest that MDM2-dependent recruitment of methyltransferases is a novel mechanism of p53 regulation through methylation of both p53 itself and histone H3 at target promoters.


Assuntos
Regulação da Expressão Gênica , Histona-Lisina N-Metiltransferase/metabolismo , Metiltransferases/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas Repressoras/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Células Cultivadas , Histona-Lisina N-Metiltransferase/genética , Histonas/genética , Histonas/metabolismo , Humanos , Lisina/genética , Lisina/metabolismo , Metilação , Metiltransferases/genética , Camundongos , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/deficiência , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Repressoras/genética , Estresse Fisiológico , Transcrição Gênica , Proteína Supressora de Tumor p53/deficiência
7.
Methods Mol Biol ; 462: 201-11, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19160671

RESUMO

This chapter describes methods for studying downstream events of the PI3K/Akt signaling cascade, focusing on the FoxO transcription factors. These approaches also represent alternative means for gauging the phosphoinositide-3 kinase/Akt activity. We describe protocols for the fractionation of cytoplasmic and nuclear protein extracts and for studying transcription factor DNA-binding activity in vitro and in vivo.


Assuntos
DNA/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Espaço Intracelular/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Sequência de Bases , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Precipitação Química , Imunoprecipitação da Cromatina , Citosol/metabolismo , DNA/genética , Humanos , Proteínas Nucleares/metabolismo , Reação em Cadeia da Polimerase , Transporte Proteico , Sonicação
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