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1.
Cell Rep ; 27(12): 3547-3560.e5, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31130414

RESUMO

Orchestrating cell-cycle-dependent mRNA oscillations is critical to cell proliferation in multicellular organisms. Even though our understanding of cell-cycle-regulated transcription has improved significantly over the last three decades, the mechanisms remain untested in vivo. Unbiased transcriptomic profiling of G0, G1-S, and S-G2-M sorted cells from FUCCI mouse embryos suggested a central role for E2Fs in the control of cell-cycle-dependent gene expression. The analysis of gene expression and E2F-tagged knockin mice with tissue imaging and deep-learning tools suggested that post-transcriptional mechanisms universally coordinate the nuclear accumulation of E2F activators (E2F3A) and canonical (E2F4) and atypical (E2F8) repressors during the cell cycle in vivo. In summary, we mapped the spatiotemporal expression of sentinel E2F activators and canonical and atypical repressors at the single-cell level in vivo and propose that two distinct E2F modules relay the control of gene expression in cells actively cycling (E2F3A-8-4) and exiting the cycle (E2F3A-4) during mammalian development.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Ciclo Celular , Diferenciação Celular , Fator de Transcrição E2F3/fisiologia , Fator de Transcrição E2F4/fisiologia , Regulação da Expressão Gênica , Proteínas Repressoras/fisiologia , Animais , Proteínas de Ciclo Celular/genética , Proliferação de Células , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Knockout , Regiões Promotoras Genéticas , Transcriptoma
2.
Anticancer Drugs ; 17(10): 1171-7, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17075316

RESUMO

In the process of acquired drug resistance, the absence of tumour cell subpopulations already resistant before treatment implies an initial adaptive stage of cell growth following drug exposure that, under the selective pressure of the drug, allows the emergence of stably resistant cell variants. Here, we show that p53-defective HT-29 colon cancer cells overcome methotrexate-induced cell death owing to DNA damage checkpoint-mediated cell survival at the adaptive stage that precedes stable resistance acquisition. HT-29 cell cycle progression was dramatically delayed in the presence of a lethal dose of methotrexate, leading to DNA damage during S-phase transition and to cell death as treated cells progressed to G2 and M phases. As a result, the DNA damage checkpoint was induced as indicated by the presence of activated phosphorylated forms of checkpoint proteins Chk1 and Rad9. As we recently described, in-vitro resistance to methotrexate occurs without cell subpopulations already resistant before treatment, hence resistance is acquired through a multistep process that includes an early stage of transient cell survival. Our present results showed that this acute cell survival stage was due to a minor percentage of cells that could complete the first division cycle after drug exposure. Cell survival was enhanced by drug withdrawal during S-phase transition and suppressed if drug withdrawal was followed by treatment with the checkpoint-inhibitor drug caffeine. These results thus point to checkpoint-mediated transient adaptation as a target to prevent the emergence of acquired resistance to methotrexate.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Metotrexato/farmacologia , Proteínas Quinases/metabolismo , Proteínas Quinases/fisiologia , Antimetabólitos Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Quinase 1 do Ponto de Checagem , Dano ao DNA/efeitos dos fármacos , Células HT29 , Histonas/metabolismo , Humanos , Modelos Biológicos , Neoplasia Residual , Fosforilação/efeitos dos fármacos
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