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首页> 外文期刊>Molecular and Cellular Biology >Involvement of Myc Activity in a G1/S-Promoting Mechanism Parallel to the pRb/E2F Pathway
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Involvement of Myc Activity in a G1/S-Promoting Mechanism Parallel to the pRb/E2F Pathway

机译：Myc活性参与与pRb / E2F途径平行的G1 / S促进机制。

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The retinoblastoma protein (pRb)/E2F pathway regulates commitment of mammalian cells to replicate DNA. On the other hand, mitogen-stimulated cells deprived of E2F activity can still maintain physiologically relevant levels of cyclin E-dependent kinase activity and gradually enter S phase, suggesting the existence of a DNA synthesis-inducing mechanism parallel to the pRb/E2F axis. Here we show that regulatable ectopic expression of cyclin E or transcriptionally active Myc can rapidly induce DNA synthesis in U2OS-derived cell lines whose E2F activity is blocked by a constitutively active pRb (pRbΔcdk) mutant. The effect of Myc is associated with Cdc25A phosphatase and cyclin E-CDK2 kinase activation and abolished by antagonizing Myc activity with the dominant-negative (dn) MadMyc chimera. Moreover, while abrogation of either endogenous E2F or Myc activity only delays and lowers DNA synthesis in synchronized U2OS cells or rat diploid fibroblasts, concomitant neutralization of both abolishes it. Whereas ectopic Myc and E2F1 rescue the G1/S delay caused by pRbΔcdk (or dnDP1) and MadMyc, respectively, cyclin E or Cdc25A can restore DNA replication even in cells concomitantly exposed to pRbΔcdk and MadMyc. However, coexpression of dnCDK2 neutralizes all of these rescuing effects. Finally, proper transcription of cyclin E and Cdc25A at the G1/S transition requires both Myc and E2F activities, and subthreshold levels of ectopic cyclin E and Cdc25A synergistically restore DNA synthesis in cells with silenced Myc and E2F activities. These results suggest that Myc controls a G1/S-promoting mechanism regulating cyclin E-CDK2 in parallel to the “classical” pRb/E2F pathway.
机译：视网膜母细胞瘤蛋白（pRb）/ E2F途径调节哺乳动物细胞复制DNA的作用。另一方面，缺乏E2F活性的促有丝分裂原刺激的细胞仍可以维持细胞周期蛋白E依赖性激酶活性的生理相关水平并逐渐进入S期，这表明存在与pRb / E2F轴平行的DNA合成诱导机制。在这里，我们显示出细胞周期蛋白E或转录活性Myc的可调控异位表达可以在U2OS衍生的细胞系（其E2F活性被组成性活性pRb（pRbΔcdk）突变体阻止）中快速诱导DNA合成。 Myc的作用与Cdc25A磷酸酶和细胞周期蛋白E-CDK2激酶活化有关，并通过与显性阴性（dn）MadMyc嵌合体拮抗Myc活性而被取消。此外，虽然废除内源性E2F或Myc活性只会延迟并降低同步U2OS细胞或大鼠二倍体成纤维细胞中的DNA合成，但两者的中和作用都将其废除。异位Myc和E2F1分别缓解了pRbΔcdk（或dnDP1）和MadMyc引起的G 1 / S延迟，而即使在同时暴露于pRbΔcdk和MadMyc的细胞中，细胞周期蛋白E或Cdc25A也可以恢复DNA复制。但是，dnCDK2的共表达中和了所有这些拯救作用。最后，细胞周期蛋白E和Cdc25A在G 1 / S过渡过程中的正确转录需要Myc和E2F活性，而异位细胞周期蛋白E和Cdc25A的亚阈值水平可协同恢复沉默的Myc和E2F细胞的DNA合成活动。这些结果表明，Myc控制了G 1 / S促进机制，与“经典” pRb / E2F途径平行调节细胞周期蛋白E-CDK2。

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