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p53 Activates the Long Noncoding RNA Pvt1b to Inhibit Myc and Suppress Tumorigenesis.

P53 激活长链非编码 RNA Pvt1b 抑制 Myc,抑制肿瘤发生。

  • 影响因子:11.82
  • DOI:10.1016/j.molcel.2019.12.014
  • 作者列表:"Olivero CE","Martínez-Terroba E","Zimmer J","Liao C","Tesfaye E","Hooshdaran N","Schofield JA","Bendor J","Fang D","Simon MD","Zamudio JR","Dimitrova N
  • 发表时间:2020-02-20
Abstract

:The tumor suppressor p53 transcriptionally activates target genes to suppress cellular proliferation during stress. p53 has also been implicated in the repression of the proto-oncogene Myc, but the mechanism has remained unclear. Here, we identify Pvt1b, a p53-dependent isoform of the long noncoding RNA (lncRNA) Pvt1, expressed 50 kb downstream of Myc, which becomes induced by DNA damage or oncogenic signaling and accumulates near its site of transcription. We show that production of the Pvt1b RNA is necessary and sufficient to suppress Myc transcription in cis without altering the chromatin organization of the locus. Inhibition of Pvt1b increases Myc levels and transcriptional activity and promotes cellular proliferation. Furthermore, Pvt1b loss accelerates tumor growth, but not tumor progression, in an autochthonous mouse model of lung cancer. These findings demonstrate that Pvt1b acts at the intersection of the p53 and Myc transcriptional networks to reinforce the anti-proliferative activities of p53.

摘要

肿瘤抑制因子 p53 在应激过程中转录激活靶基因抑制细胞增殖。p53 也与原癌基因 Myc 的抑制有关,但机制尚不清楚。在这里,我们鉴定了 Pvt1b,长链非编码 RNA (lncRNA) Pvt1 的 p53-dependent 亚型,在 Myc 下游表达 50kb, 由 DNA 损伤或致癌信号诱导,并在其转录位点附近积累。我们证明 Pvt1b RNA 的产生是必要的,并且足以抑制 cis 中的 Myc 转录,而不改变位点的染色质组织。抑制 Pvt1b 增加 Myc 水平和转录活性,促进细胞增殖。此外,在肺癌的自体小鼠模型中,Pvt1b 丢失加速肿瘤生长,但不加速肿瘤进展。这些发现证明 Pvt1b 作用于 p53 和 Myc 转录网络的交叉点,加强 p53 的抗增殖活性。

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影响因子:4.88
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影响因子:6.50
发表时间:2020-03-31
来源期刊:Cancer letters
DOI:10.1016/j.canlet.2019.12.039
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