Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Mais filtros

Base de dados
Tipo de documento
Assunto da revista
Intervalo de ano de publicação
1.
Cell ; 133(6): 1019-31, 2008 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-18555778

RESUMO

Oncogene-induced cellular senescence (OIS) is emerging as a potent cancer-protective response to oncogenic events, serving to eliminate early neoplastic cells from the proliferative pool. Using combined genetic and bioinformatic analysis, we find that OIS is linked specifically to the activation of an inflammatory transcriptome. Induced genes included the pleiotropic cytokine interleukin-6 (IL-6), which upon secretion by senescent cells acted mitogenically in a paracrine fashion. Unexpectedly, IL-6 was also required for the execution of OIS, but in a cell-autonomous mode. Its depletion caused the inflammatory network to collapse and abolished senescence entry and maintenance. Furthermore, we demonstrate that the transcription factor C/EBPbeta cooperates with IL-6 to amplify the activation of the inflammatory network, including IL-8. In human colon adenomas, IL-8 specifically colocalized with arrested, p16(INK4A)-positive epithelium. We propose a model in which the context-dependent cytostatic and promitogenic functions of specific interleukins contribute to connect senescence with an inflammatory phenotype and cancer.


Assuntos
Senescência Celular , Inflamação , Interleucina-6/metabolismo , Adenoma/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proliferação de Células , Neoplasias do Colo/metabolismo , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Perfilação da Expressão Gênica , Heterocromatina , Humanos , Interleucina-8/metabolismo , Interferência de RNA , Regulação para Cima
2.
Genes Dev ; 26(10): 1055-69, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22549727

RESUMO

Human melanocytic nevi (moles) are benign lesions harboring activated oncogenes, including BRAF. Although this oncogene initially acts mitogenically, eventually, oncogene-induced senescence (OIS) ensues. Nevi can infrequently progress to melanomas, but the mechanistic relationship with OIS is unclear. We show here that PTEN depletion abrogates BRAF(V600E)-induced senescence in human fibroblasts and melanocytes. Correspondingly, in established murine BRAF(V600E)-driven nevi, acute shRNA-mediated depletion of PTEN prompted tumor progression. Furthermore, genetic analysis of laser-guided microdissected human contiguous nevus-melanoma specimens recurrently revealed identical mutations in BRAF or NRAS in adjacent benign and malignant melanocytes. The PI3K pathway was often activated through either decreased PTEN or increased AKT3 expression in melanomas relative to their adjacent nevi. Pharmacologic PI3K inhibition in melanoma cells suppressed proliferation and induced the senescence-associated tumor suppressor p15(INK4B). This treatment also eliminated subpopulations resistant to targeted BRAF(V600E) inhibition. Our findings suggest that a significant proportion of melanomas arise from nevi. Furthermore, these results demonstrate that PI3K pathway activation serves as a rate-limiting event in this setting, acting at least in part by abrogating OIS. The reactivation of senescence features and elimination of cells refractory to BRAF(V600E) inhibition by PI3K inhibition warrants further investigation into the therapeutic potential of simultaneously targeting these pathways in melanoma.


Assuntos
Senescência Celular , Melanoma/patologia , Nevo/patologia , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias Cutâneas/patologia , Substituição de Aminoácidos , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p15/metabolismo , Ativação Enzimática , Fibroblastos/metabolismo , Fibroblastos/patologia , Ácido Glutâmico/genética , Ácido Glutâmico/metabolismo , Humanos , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/metabolismo , Nevo/metabolismo , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Cutâneas/metabolismo , Valina/genética , Valina/metabolismo
3.
Nature ; 436(7051): 720-4, 2005 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-16079850

RESUMO

Most normal mammalian cells have a finite lifespan, thought to constitute a protective mechanism against unlimited proliferation. This phenomenon, called senescence, is driven by telomere attrition, which triggers the induction of tumour suppressors including p16(INK4a) (ref. 5). In cultured cells, senescence can be elicited prematurely by oncogenes; however, whether such oncogene-induced senescence represents a physiological process has long been debated. Human naevi (moles) are benign tumours of melanocytes that frequently harbour oncogenic mutations (predominantly V600E, where valine is substituted for glutamic acid) in BRAF, a protein kinase and downstream effector of Ras. Nonetheless, naevi typically remain in a growth-arrested state for decades and only rarely progress into malignancy (melanoma). This raises the question of whether naevi undergo BRAF(V600E)-induced senescence. Here we show that sustained BRAF(V600E) expression in human melanocytes induces cell cycle arrest, which is accompanied by the induction of both p16(INK4a) and senescence-associated acidic beta-galactosidase (SA-beta-Gal) activity, a commonly used senescence marker. Validating these results in vivo, congenital naevi are invariably positive for SA-beta-Gal, demonstrating the presence of this classical senescence-associated marker in a largely growth-arrested, neoplastic human lesion. In growth-arrested melanocytes, both in vitro and in situ, we observed a marked mosaic induction of p16(INK4a), suggesting that factors other than p16(INK4a) contribute to protection against BRAF(V600E)-driven proliferation. Naevi do not appear to suffer from telomere attrition, arguing in favour of an active oncogene-driven senescence process, rather than a loss of replicative potential. Thus, both in vitro and in vivo, BRAF(V600E)-expressing melanocytes display classical hallmarks of senescence, suggesting that oncogene-induced senescence represents a genuine protective physiological process.


Assuntos
Ciclo Celular , Senescência Celular , Nevo/metabolismo , Nevo/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Linhagem Celular , Proliferação de Células , Inibidor p16 de Quinase Dependente de Ciclina/deficiência , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Fibroblastos , Humanos , Hibridização in Situ Fluorescente , Lactente , Melanócitos/patologia , Nevo/congênito , Nevo/genética , Telômero/genética , Telômero/metabolismo , beta-Galactosidase/metabolismo
4.
Carcinogenesis ; 31(2): 201-7, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19942610

RESUMO

Mutant RAS (RAS(V12)) is known to transform most immortal cells but to induce premature senescence in primary cells. RAS(V12)-induced senescence in murine cells depends on the induction of the ARF/p53 and the retinoblastoma (Rb) family tumor suppressor pathways. We and others have shown previously that oncogene-induced senescence in vitro can be used as a tool to identify new cancer-related genes. In addition, we have shown that oncogene-induced senescence corresponds to an in vivo tumor suppressive mechanism. Therefore, we extended our search for novel genes that bypass of RAS(V12)-induced senescence, with the help of a previously designed unbiased functional screen with cDNA expression libraries. In this screen, we expected to find new mediators feeding into the p53 or Rb pathways or novel signaling factors. We report here the identification of leukemia/lymphoma related factor (Lrf) encoding a transcription factor with a BTB/POZ domain and Krüppel-like zinc fingers. This gene was previously identified as a potential oncogene that is overexpressed in human cancer. We find that LRF enhances E2F-dependent transcription and that it synergizes with RAS(V12) in activating E2F. Indeed, LRF-mediated bypass of RAS(V12)-induced senescence is accompanied by the induction of several E2F-target genes, including Cyclin E, Cyclin A and p107. Unexpectedly, LRF exerted this activity independent of several critical senescence inducers, such as p19(ARF), p21(CIP) and p16(INK4A). We show that CYCLIN E is necessary for LRF-mediated bypass, suggesting that it corresponds to a critical mediator of LRF-driven oncogenic transformation. Thus, LRF bypasses RAS(V12)-induced senescence in a CYCLIN E-dependent manner, which conceivably contributes to its role in cancer.


Assuntos
Transformação Celular Neoplásica , Senescência Celular , Ciclina E/metabolismo , Proteínas de Ligação a DNA/metabolismo , Oncogenes/fisiologia , Proteínas Proto-Oncogênicas p21(ras)/fisiologia , Fatores de Transcrição/metabolismo , Animais , Western Blotting , Ciclina E/genética , Proteínas de Ligação a DNA/genética , Biblioteca Gênica , Humanos , Camundongos , Células NIH 3T3 , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/genética , Regulação para Cima
5.
Genes Dev ; 22(7): 884-93, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18334619

RESUMO

VHL, NF-1, c-Ret, and Succinate Dehydrogenase Subunits B and D act on a developmental apoptotic pathway that is activated when nerve growth factor (NGF) becomes limiting for neuronal progenitor cells and requires the EglN3 prolyl hydroxylase as a downstream effector. Germline mutations of these genes cause familial pheochromocytoma and other neural crest-derived tumors. Using an unbiased shRNA screen we found that the kinesin KIF1Bbeta acts downstream from EglN3 and is both necessary and sufficient for neuronal apoptosis when NGF becomes limiting. KIF1Bbeta maps to chromosome 1p36.2, which is frequently deleted in neural crest-derived tumors including neuroblastomas. We identified inherited loss-of-function KIF1Bbeta missense mutations in neuroblastomas and pheochromocytomas and an acquired loss-of-function mutation in a medulloblastoma, arguing that KIF1Bbeta is a pathogenic target of these deletions.


Assuntos
Apoptose , Cromossomos de Mamíferos/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas Imediatamente Precoces/metabolismo , Cinesinas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Animais Recém-Nascidos , Células Cultivadas , Criança , Mapeamento Cromossômico , Proteínas de Ligação a DNA/genética , Células HeLa , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia , Proteínas Imediatamente Precoces/genética , Immunoblotting , Cinesinas/genética , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos , Camundongos Knockout , Modelos Biológicos , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Neuroblastoma/genética , Neuroblastoma/patologia , Neurônios/citologia , Neurônios/metabolismo , Células PC12 , Feocromocitoma/genética , Feocromocitoma/patologia , Pró-Colágeno-Prolina Dioxigenase , Interferência de RNA , Ratos , Proteínas Supressoras de Tumor/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA