MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function
MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function
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DOI：
10.1038/cdd.2011.190
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发表时间：
2012-06-01
影响因子：
12.4
通讯作者：
Blandino, G.
中科院分区：
文献类型：
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作者：
Donzelli, S.;Fontemaggi, G.;Blandino, G.
p53突变对非小细胞肺癌（NSCLC）化疗耐药性有深远影响。突变型p53蛋白通常在肿瘤中以高水平表达，在肿瘤中它们发挥致癌功能。在这里，我们表明p53 R175 H（一种热点p53突变体）诱导microRNA（miRNA）-128-2表达。突变体p53与miR-128 -2宿主基因ARPP 21的推定启动子结合，决定ARPP 21 mRNA和miR-128-2的伴随诱导。肺癌细胞中的miR-128-2表达抑制细胞凋亡并赋予对顺铂、阿霉素和5-氟尿嘧啶治疗的增加的抗性。在分子水平上，miR-128-2在转录后靶向E2 F5，并导致其对p21（waf 1）转录的抑制活性的消除。p21（WAF 1）蛋白定位于细胞质区室，在那里它通过阻止胱天蛋白酶原-3裂解而发挥抗凋亡作用。这项研究强调了miRNA-128-2作为NSCLC化疗耐药性的主要调节因子的作用。Cell Death and Differentiation（2012）19，1038-1048; doi：10.1038/cdd.2011.190; 2011年12月23日在线发表
p53 mutations have profound effects on non-small-cell lung cancer (NSCLC) resistance to chemotherapeutic treatments. Mutant p53 proteins are usually expressed at high levels in tumors, where they exert oncogenic functions. Here we show that p53R175H, a hotspot p53 mutant, induces microRNA (miRNA)-128-2 expression. Mutant p53 binds to the putative promoter of miR128-2 host gene, ARPP21, determining a concomitant induction of ARPP21 mRNA and miR-128-2. miR-128-2 expression in lung cancer cells inhibits apoptosis and confers increased resistance to cisplatin, doxorubicin and 5-fluorouracyl treatments. At the molecular level, miR-128-2 post-transcriptionally targets E2F5 and leads to the abrogation of its repressive activity on p21(waf1) transcription. p21(waf1) protein localizes to the cytoplasmic compartment, where it exerts an anti-apoptotic effect by preventing pro-caspase-3 cleavage. This study emphasizes miRNA-128-2 role as a master regulator in NSCLC chemoresistance. Cell Death and Differentiation (2012) 19, 1038-1048; doi:10.1038/cdd.2011.190; published online 23 December 2011