PDCD4 controls the G1/S-phase transition in a telomerase-immortalized epithelial cell line and affects the expression level and translation of multiple mRNAs
PDCD4 controls the G1/S-phase transition in a telomerase-immortalized epithelial cell line and affects the expression level and translation of multiple mRNAs
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DOI：
10.1038/s41598-020-59678-w
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发表时间：
2020-02-17
影响因子：
4.6
通讯作者：
Klempnauer, Karl-Heinz
中科院分区：
文献类型：
--
作者：
Haas, Astrid;Nilges, Benedikt S.;Klempnauer, Karl-Heinz
PDCD 4是由肿瘤抑制基因PDCD 4（程序性细胞死亡4）编码的蛋白质，其通过调节特定转录因子的活性和抑制具有结构化5 '-UTR的mRNA的翻译而参与细胞转录和翻译的控制。大多数人PDCD 4的研究都采用了肿瘤细胞系，这可能导致其在正常细胞中的作用存在偏见。在这里，我们研究了PDCD 4在端粒酶永生化的人上皮细胞系中的功能。我们首次表明PDCD 4是G1/S转换所必需的，证明了它在细胞周期中的关键作用。抑制p53依赖的p21激活（WAF 1/CIP 1）超越了PDCD 4对G1/S转换的要求，表明PDCD 4抵消了基础p53活性，以防止p53激活G1/S检查点。转录组和核糖体分析数据显示，PDCD 4的沉默改变了许多mRNA的表达水平和翻译，提供了上皮细胞系中受PDCD 4影响的细胞过程的无偏见观点。我们的数据确定PDCD 4作为细胞周期和DNA相关功能的关键调节因子，当它被沉默时会受到抑制，这表明PDCD 4表达减少可能会通过损害基因组完整性而促进肿瘤的发展。
PDCD4, the protein encoded by the tumor suppressor gene PDCD4 (programmed cell death 4) has been implicated in the control of cellular transcription and translation by modulating the activity of specific transcription factors and suppressing the translation of mRNAs with structured 5'-UTRs. Most studies of human PDCD4 have employed tumor cell lines, possibly resulting in a biased picture of its role in normal cells. Here, we have studied the function of PDCD4 in a telomerase-immortalized human epithelial cell line. We show for the first time that PDCD4 is required for the G1/S-transition, demonstrating its crucial role in the cell cycle. Inhibition of p53-dependent activation of p21(WAF1/CIP1) overrides the requirement for PDCD4 for the G1/S-transition, suggesting that PDCD4 counteracts basal p53 activity to prevent activation of the G1/S checkpoint by p53. Transcriptome and ribosome profiling data show that silencing of PDCD4 changes the expression levels and translation of many mRNAs, providing an unbiased view of the cellular processes that are affected by PDCD4 in an epithelial cell line. Our data identify PDCD4 as a key regulator of cell cycle- and DNA-related functions that are inhibited when it is silenced, suggesting that decreased expression of PDCD4 might contribute to tumor development by compromising genomic integrity.