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.

虽然猿病毒 40 (SV40) 的大 T 抗原 (LT) 通过灭活肿瘤抑制蛋白 p53 和 pRb 来促进肿瘤发生，但 SV40 小 T 抗原 (ST) 被认为在这一过程中是可有可无的。然而，在这里我们表明，LT 促进表达致癌 Ras 的人类细胞中的致癌生长和衰老，并且后一种效应被 ST 拮抗。LT 单独使 p53 失活促进了衰老相关分泌表型 (SASP)，而 ST 的额外表达减弱了这种表型，允许细胞避免致癌基因诱导的衰老 (OIS)，从而促进有效的肿瘤发生。ST 与异染色质蛋白 1 结合蛋白 3 (HP1BP3) 相互作用并抑制其功能，HP1BP3 是全球 microRNA 生物发生的正调节因子，从而触发 B 细胞易位基因 2 (BTG2) 的异常上调，这对于 ST 预防 SASP 和 OIS 至关重要。总的来说，我们的结果表明，HP1BP3-BTG2 轴构成了一个故障安全系统，通过 OIS 诱导来防止肿瘤发生，并且该系统被 ST 劫持。