A fail-safe system to prevent oncogenesis by senescence is targeted by SV40 small T antigen
A fail-safe system to prevent oncogenesis by senescence is targeted by SV40 small T antigen
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DOI：
10.1038/s41388-019-1139-1
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发表时间：
2019-12
期刊：
影响因子：
8
通讯作者：
K. Oshikawa;M. Matsumoto;M. Kodama;Hideyuki Shimizu;K. Nakayama
中科院分区：
文献类型：
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作者：
K. Oshikawa;M. Matsumoto;M. Kodama;Hideyuki Shimizu;K. Nakayama
猴病毒40(SV40)的大T抗原(LT)通过灭活抑癌蛋白P53和pRB来促进肿瘤的发生，而SV40的小T抗原(ST)则被认为在这一过程中是必不可少的。然而，我们在这里表明LT促进了表达致癌RAS的人细胞的致癌生长和衰老，而后者的作用被ST拮抗。单独用LT灭活P53可促进衰老相关分泌表型(SASP)，而ST的额外表达可减弱这一表型，使细胞避免癌基因诱导的衰老(OIS)，从而促进有效的肿瘤发生。ST与全球microRNA生物发生的正调控因子异染色质蛋白1结合蛋白3(HP1BP3)相互作用并抑制其功能，从而触发B细胞易位基因2(BTG2)的异常上调，这是ST预防SASP和OIS所必需的。综上所述，我们的结果表明，HP1BP3-BTG2轴通过OIS诱导构成了防止肿瘤发生的故障安全系统，并且该系统被ST劫持。
Whereas large T antigen (LT) of simian virus 40 (SV40) promotes oncogenesis by inactivating the tumor suppressor proteins p53 and pRb, SV40 small T antigen (ST) has been thought to be dispensable for this process. However, here we show that LT promotes both oncogenic growth and senescence in human cells expressing oncogenic Ras and that this latter effect is antagonized by ST. Inactivation of p53 by LT alone promoted the senescence-associated secretory phenotype (SASP), whereas the additional expression of ST attenuated this phenotype, allowing cells to avoid oncogene-induced senescence (OIS) and thereby promoting efficient oncogenesis. ST interacts with and inhibits the function of heterochromatin protein 1–binding protein 3 (HP1BP3), a positive regulator of global microRNA biogenesis, and it thereby triggers aberrant upregulation of B-cell translocation gene 2 (BTG2), which is essential for prevention of SASP and OIS by ST. Collectively, our results indicate that the HP1BP3-BTG2 axis constitutes a fail-safe system to prevent oncogenesis by means of OIS induction, and that this system is hijacked by ST.