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1.
Cancer Cell ; 23(5): 634-46, 2013 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-23680148

RESUMO

The tumor suppressor p53 is frequently mutated in human cancer. Common mutant p53 (mutp53) isoforms can actively promote cancer through gain-of-function (GOF) mechanisms. We report that mutp53 prolongs TNF-α-induced NF-κB activation in cultured cells and intestinal organoid cultures. Remarkably, when exposed to dextran sulfate sodium, mice harboring a germline p53 mutation develop severe chronic inflammation and persistent tissue damage, and are highly prone to inflammation-associated colon cancer. This mutp53 GOF is manifested by rapid onset of flat dysplastic lesions that progress to invasive carcinoma with mutp53 accumulation and augmented NF-κB activation, faithfully recapitulating features frequently observed in human colitis-associated colorectal cancer (CAC). These findings might explain the early appearance of p53 mutations in human CAC.


Assuntos
Neoplasias Colorretais/genética , NF-kappa B/fisiologia , Proteína Supressora de Tumor p53/genética , Animais , Azoximetano , Colite/induzido quimicamente , Colite/complicações , Colite/genética , Colo/metabolismo , Colo/patologia , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Dano ao DNA , Sulfato de Dextrana , Predisposição Genética para Doença , Histonas/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Isoformas de Proteínas/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/fisiologia , Proteína Supressora de Tumor p53/fisiologia
2.
Mol Cell ; 46(5): 662-73, 2012 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-22681888

RESUMO

Embryonic stem cells (ESCs) maintain high genomic plasticity, which is essential for their capacity to enter diverse differentiation pathways. Posttranscriptional modifications of chromatin histones play a pivotal role in maintaining this plasticity. We now report that one such modification, monoubiquitylation of histone H2B on lysine 120 (H2Bub1), catalyzed by the E3 ligase RNF20, increases during ESC differentiation and is required for efficient execution of this process. This increase is particularly important for the transcriptional induction of relatively long genes during ESC differentiation. Furthermore, we identify the deubiquitinase USP44 as a negative regulator of H2B ubiquitylation, whose downregulation during ESC differentiation contributes to the increase in H2Bub1. Our findings suggest that optimal ESC differentiation requires dynamic changes in H2B ubiquitylation patterns, which must occur in a timely and well-coordinated manner.


Assuntos
Diferenciação Celular/genética , Células-Tronco Embrionárias/citologia , Endopeptidases/fisiologia , Histonas/metabolismo , Ubiquitina-Proteína Ligases/fisiologia , Animais , Montagem e Desmontagem da Cromatina , Regulação para Baixo , Células-Tronco Embrionárias/metabolismo , Endopeptidases/metabolismo , Epigênese Genética , Humanos , Camundongos , Modelos Genéticos , Ubiquitina-Proteína Ligases/metabolismo , Proteases Específicas de Ubiquitina , Ubiquitinação
3.
Mol Cell ; 45(2): 222-32, 2012 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-22284678

RESUMO

Members of the ß-karyopherin family mediate nuclear import of ribosomal proteins and export of ribosomal subunits, both required for ribosome biogenesis. We report that transcription of the ß-karyopherin genes importin 7 (IPO7) and exportin 1 (XPO1), and several additional nuclear import receptors, is regulated positively by c-Myc and negatively by p53. Partial IPO7 depletion triggers p53 activation and p53-dependent growth arrest. Activation of p53 by IPO7 knockdown has distinct features of ribosomal biogenesis stress, with increased binding of Mdm2 to ribosomal proteins L5 and L11 (RPL5 and RPL11). Furthermore, p53 activation is dependent on RPL5 and RPL11. Of note, IPO7 and XPO1 are frequently overexpressed in cancer. Altogether, we propose that c-Myc and p53 counter each other in the regulation of elements within the nuclear transport machinery, thereby exerting opposing effects on the rate of ribosome biogenesis. Perturbation of this balance may play a significant role in promoting cancer.


Assuntos
Carioferinas/fisiologia , Proteínas Proto-Oncogênicas c-myc/fisiologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Ribossomos/metabolismo , Proteína Supressora de Tumor p53/fisiologia , Transporte Ativo do Núcleo Celular , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Carioferinas/genética , Carioferinas/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Proteínas Ribossômicas/metabolismo , Estresse Fisiológico , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteína Exportina 1
4.
Proc Natl Acad Sci U S A ; 107(43): 18511-6, 2010 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-20937856

RESUMO

The p53 tumor suppressor is mutated in a high percentage of human tumors. However, many other tumors retain wild-type (wt) p53 expression, raising the intriguing possibility that they actually benefit from it. Recent studies imply a role for p53 in regulation of autophagy, a catabolic pathway by which eukaryotic cells degrade and recycle macromolecules and organelles, particularly under conditions of nutrient deprivation. Here, we show that, in many cell types, p53 confers increased survival in the face of chronic starvation. We implicate regulation of autophagy in this effect. In HCT116 human colorectal cancer cells exposed to prolonged nutrient deprivation, the endogenous wt p53 posttranscriptionally down-regulates LC3, a pivotal component of the autophagic machinery. This enables reduced, yet sustainable autophagic flux. Loss of p53 impairs autophagic flux and causes excessive LC3 accumulation upon starvation, culminating in apoptosis. Thus, p53 increases cell fitness by maintaining better autophagic homeostasis, adjusting the rate of autophagy to changing circumstances. We propose that some cancer cells retain wt p53 to benefit from the resultant increased fitness under limited nutrient supply.


Assuntos
Sobrevivência Celular/fisiologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Proteínas Associadas aos Microtúbulos/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Autofagia/fisiologia , Sequência de Bases , Linhagem Celular Tumoral , Meios de Cultura , Primers do DNA/genética , Regulação para Baixo , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Genes p53 , Humanos , Microscopia Eletrônica de Transmissão , Proteínas Associadas aos Microtúbulos/genética , Fagossomos/metabolismo , Fagossomos/ultraestrutura , Processamento de Proteína Pós-Traducional , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética
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