p63 is required beside p53 for PERP-mediated apoptosis in uveal melanoma.
p63 is required beside p53 for PERP-mediated apoptosis in uveal melanoma.
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DOI：
10.1038/bjc.2016.269
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发表时间：
2016-10-11
影响因子：
8.8
通讯作者：
Paraoan, Luminita
中科院分区：
文献类型：
--
作者：
Awais, Raheela;Spiller, David G.;White, Michael R. H.;Paraoan, Luminita
PERP（p53 apoptosis effector related to PMP-22）是p53的一个转录靶点，在葡萄膜黑色素瘤（UM）中表达下调，并参与细胞凋亡的损害。有趣的是，尽管有功能性p53，但在UM中不诱导PERP。位于3号染色体上的p63在高危UM中发生特征性改变，可以反式激活PERP。在这里，我们确定了p63表达的功能作用，在启动p53/PERP介导的细胞凋亡在UM。通过定量PCR（qPCR）和免疫印迹法在用DNA损伤剂处理的UM细胞系中监测PERP表达。通过p63-tGFP（p63-tGFP）在抗凋亡的3q缺陷型OCM-1细胞中的瞬时表达来评估p63的功能作用。通过qPCR、免疫印迹和活细胞共聚焦显微镜表征p63、PERP和p53的表达和定位以及细胞凋亡的诱导。在所有UM细胞系中，PERP表达显著下调。DNA损伤治疗未能诱导细胞凋亡和激活PERP在OCM-1细胞，显示非功能水平的p63。p63-tGFP的表达诱导细胞凋亡，PERP表达和相关的p53积累显著增加。p63的缺乏导致UM中PERP水平降低和p53介导的细胞凋亡受损。p63表达是UM中PERP介导的凋亡所必需的。
PERP (p53 apoptosis effector related to PMP-22), a transcriptional target of p53, is downregulated and contributes to the impairment of apoptosis in uveal melanoma (UM). Intriguingly, PERP is not induced in UM despite functional p53. p63, located on chromosome 3, which is characteristically altered in high-risk UM, can transactivate PERP. Here, we determine the functional role of p63 expression in the initiation of p53/PERP-mediated apoptosis in UM. PERP expression was monitored by quantitative PCR (qPCR) and immunoblotting in UM cell lines treated with DNA-damaging agents. The functional role of p63 was assessed by transient expression of p63-turbo GFP (p63-tGFP) in the apoptosis- resistant, 3q-deficient OCM-1 cells. Expression and localisation of p63, PERP and p53, and induction of apoptosis were characterised by qPCR, immunoblotting and live cell confocal microscopy. PERP expression was significantly downregulated in all UM cell lines. DNA-damaging treatments failed to induce apoptosis and activate PERP in OCM-1 cells, which displayed non-functional levels of p63. Expression of p63-tGFP induced apoptosis with marked increase in PERP expression and associated p53 accumulation. Lack of p63 contributes to reduced PERP levels and impaired p53-mediated apoptosis in UM. p63 expression is required for PERP-mediated apoptosis in UM.
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影响因子：
64.8
作者：
Mills, AA;Zheng, BH;Bradley, A
通讯作者：
Bradley, A
影响因子：
4.2
作者：
Kishore, K;Ghazvini, S;Selle, J
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4.4
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Maat, Willem;Beiboer, Sigrid H. W.;van der Velden, Pieter A.
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van der Velden, Pieter A.
影响因子：
4.2
作者：
Albert, DM
通讯作者：
Albert, DM
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3.4
作者：
Nareyeck, Gordon;Zeschnigk, Michael;Anastassiou, Gerasimos
通讯作者：
Anastassiou, Gerasimos