Translational Control Protein 80 Stimulates IRES-Mediated Translation of p53 mRNA in Response to DNA Damage.
Translational Control Protein 80 Stimulates IRES-Mediated Translation of p53 mRNA in Response to DNA Damage.
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DOI：
10.1155/2015/708158
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发表时间：
2015
影响因子：
--
通讯作者：
Yang DQ
中科院分区：
文献类型：
--
作者：
Halaby MJ;Li Y;Harris BR;Jiang S;Miskimins WK;Cleary MP;Yang DQ
DNA损伤后，P53抑癌基因的合成增加。这种P53的增加和随后的激活对于保护正常细胞免受肿瘤的发生是必不可少的。我们先前发现了一个位于P53基因5‘-非翻译区的内部核糖体进入位点(IRES)，并发现DNA损伤后IRES活性增加。然而，IRES介导的P53翻译反应DNA损伤的机制仍然知之甚少。在这项研究中，我们发现翻译控制蛋白80(TCP80)在DNA损伤后与体内P53基因的结合增加。TCP80的过表达还导致P53 IRES活性增加，以应对DNA损伤。在DNA损伤后，TCP80与RNA解旋酶A(RHA)的结合增加，TCP80的过度表达与RHA一起导致P53表达增强。此外，我们还发现，TCP80和RHA表达降低的MCF-7乳腺癌细胞在DNA损伤后出现了P53诱导缺陷，其下游靶标PUMA的表达减少。综上所述，我们发现TCP80和RHA在DNA损伤后调控P53 IRES和P53诱导中的功能，为更好地理解IRES介导的P53翻译响应遗传毒性应激的机制提供了更好的理解。
Synthesis of the p53 tumor suppressor increases following DNA damage. This increase and subsequent activation of p53 are essential for the protection of normal cells against tumorigenesis. We previously discovered an internal ribosome entry site (IRES) that is located at the 5′-untranslated region (UTR) of p53 mRNA and found that the IRES activity increases following DNA damage. However, the mechanism underlying IRES-mediated p53 translation in response to DNA damage is still poorly understood. In this study, we discovered that translational control protein 80 (TCP80) has increased binding to the p53 mRNA in vivo following DNA damage. Overexpression of TCP80 also leads to increased p53 IRES activity in response to DNA damage. TCP80 has increased association with RNA helicase A (RHA) following DNA damage and overexpression of TCP80, along with RHA, leads to enhanced expression of p53. Moreover, we found that MCF-7 breast cancer cells with decreased expression of TCP80 and RHA exhibit defective p53 induction following DNA damage and diminished expression of its downstream target PUMA, a proapoptotic protein. Taken together, our discovery of the function of TCP80 and RHA in regulating p53 IRES and p53 induction following DNA damage provides a better understanding of the mechanisms that regulate IRES-mediated p53 translation in response to genotoxic stress.