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1.
Proc Natl Acad Sci U S A ; 113(34): E5024-33, 2016 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-27503890

RESUMO

Oncogene-induced senescence (OIS) is a critical tumor-suppressing mechanism that restrains cancer progression at premalignant stages, in part by causing telomere dysfunction. Currently it is unknown whether this proliferative arrest presents a stable and therefore irreversible barrier to cancer progression. Here we demonstrate that cells frequently escape OIS induced by oncogenic H-Ras and B-Raf, after a prolonged period in the senescence arrested state. Cells that had escaped senescence displayed high oncogene expression levels, retained functional DNA damage responses, and acquired chromatin changes that promoted c-Myc-dependent expression of the human telomerase reverse transcriptase gene (hTERT). Telomerase was able to resolve existing telomeric DNA damage response foci and suppressed formation of new ones that were generated as a consequence of DNA replication stress and oncogenic signals. Inhibition of MAP kinase signaling, suppressing c-Myc expression, or inhibiting telomerase activity, caused telomere dysfunction and proliferative defects in cells that had escaped senescence, whereas ectopic expression of hTERT facilitated OIS escape. In human early neoplastic skin and breast tissue, hTERT expression was detected in cells that displayed features of senescence, suggesting that reactivation of telomerase expression in senescent cells is an early event during cancer progression in humans. Together, our data demonstrate that cells arrested in OIS retain the potential to escape senescence by mechanisms that involve derepression of hTERT expression.


Assuntos
Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Proteína Oncogênica p21(ras)/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Telomerase/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Senescência Celular , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Masculino , Proteína Oncogênica p21(ras)/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Telomerase/metabolismo , Telômero/química , Telômero/metabolismo , Homeostase do Telômero
2.
EMBO J ; 31(13): 2839-51, 2012 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-22569128

RESUMO

In normal human somatic cells, telomere dysfunction causes cellular senescence, a stable proliferative arrest with tumour suppressing properties. Whether telomere dysfunction-induced senescence (TDIS) suppresses cancer growth in humans, however, is unknown. Here, we demonstrate that multiple and distinct human cancer precursor lesions, but not corresponding malignant cancers, are comprised of cells that display hallmarks of TDIS. Furthermore, we demonstrate that oncogenic signalling, frequently associated with initiating cancer growth in humans, dramatically affected telomere structure and function by causing telomeric replication stress, rapid and stochastic telomere attrition, and consequently telomere dysfunction in cells that lack hTERT activity. DNA replication stress induced by drugs also resulted in telomere dysfunction and cellular senescence in normal human cells, demonstrating that telomeric repeats indeed are hypersensitive to DNA replication stress. Our data reveal that TDIS, accelerated by oncogene-induced DNA replication stress, is a biological response of cells in human cancer precursor lesions and provide strong evidence that TDIS is a critical tumour suppressing mechanism in humans.


Assuntos
Senescência Celular/fisiologia , Oncogenes/fisiologia , Telômero/fisiologia , Linhagem Celular , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Senescência Celular/efeitos dos fármacos , Senescência Celular/genética , Replicação do DNA/efeitos dos fármacos , Replicação do DNA/genética , Replicação do DNA/fisiologia , Humanos , Oncogenes/efeitos dos fármacos , Oncogenes/genética , Inibidores da Síntese de Proteínas/farmacologia , Puromicina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Telômero/efeitos dos fármacos , Telômero/genética
3.
Cell Rep ; 42(11): 113371, 2023 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-37938972

RESUMO

Senescent cells are a major contributor to age-dependent cardiovascular tissue dysfunction, but knowledge of their in vivo cell markers and tissue context is lacking. To reveal tissue-relevant senescence biology, we integrate the transcriptomes of 10 experimental senescence cell models with a 224 multi-tissue gene co-expression network based on RNA-seq data of seven tissues biopsies from ∼600 coronary artery disease (CAD) patients. We identify 56 senescence-associated modules, many enriched in CAD GWAS genes and correlated with cardiometabolic traits-which supports universality of senescence gene programs across tissues and in CAD. Cross-tissue network analyses reveal 86 candidate senescence-associated secretory phenotype (SASP) factors, including COL6A3. Experimental knockdown of COL6A3 induces transcriptional changes that overlap the majority of the experimental senescence models, with cell-cycle arrest linked to modulation of DREAM complex-targeted genes. We provide a transcriptomic resource for cellular senescence and identify candidate biomarkers, SASP factors, and potential drivers of senescence in human tissues.


Assuntos
Senescência Celular , Transcriptoma , Humanos , Transcriptoma/genética , Senescência Celular/genética , Fenótipo , Biomarcadores , Colágeno , Colágeno Tipo VI/genética
4.
Methods Mol Biol ; 1534: 69-78, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27812868

RESUMO

Expressing oncogenes in normal somatic human cells leads to cellular senescence after just a few cell division cycles. In cells that are more resistant to culture stresses, such as human dermal fibroblasts, this oncogene-induced senescence (OIS) is a result of a DNA damage response (DDR) that is activated due to the formation of DNA lesions at both non-telomeric and telomeric DNA sequences. DNA lesions can be visualized as DDR foci by immunofluorescence microscopy using antibodies against a number of DDR factors, including ϒ-H2AX and 53BP1. Over time and as cells remain arrested in OIS, non-telomeric DDR foci progressively become resolved, while telomeric DDR foci, also called dysfunctional telomeres, persist. Here we describe a protocol to detect dysfunctional telomeres in cultured human cells, to monitor a temporal enrichment of dysfunctional telomeres in cells that had undergone OIS, and to detect dysfunctional telomeres in paraffin-embedded and formalin-fixed human tissue.


Assuntos
Senescência Celular/genética , Oncogenes/genética , Telômero/genética , Biomarcadores , Linhagem Celular Tumoral , Dano ao DNA , Fibroblastos/metabolismo , Imunofluorescência , Expressão Gênica , Vetores Genéticos/genética , Humanos , Hibridização in Situ Fluorescente , Retroviridae/genética , Transdução Genética
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