A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19ARF-p53 signaling
A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19ARF-p53 signaling
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DOI：
10.1101/gad.929302
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发表时间：
2002-03-15
影响因子：
10.5
通讯作者：
Bernards, R
中科院分区：
文献类型：
--
作者：
Shvarts, A;Brummelkamp, TR;Bernards, R
衰老限制了培养中原代细胞的增殖能力。我们在此描述一种基因筛选方法，以鉴定能够绕过这一检查点的基因。利用逆转录病毒cDNA表达文库，我们将BCL6鉴定为一种有效的衰老抑制剂。BCL6在非霍奇金淋巴瘤中经常被激活，但其作用机制一直不清楚。BCL6能有效地使原代小鼠胚胎成纤维细胞永生化，并在致癌转化中与RAS协同作用。BCL6通过一个需要诱导细胞周期蛋白D1表达的过程，克服p53下游的衰老反应，因为细胞周期蛋白D1基因敲除的成纤维细胞对BCL6诱导的永生化具有特异性抗性。我们表明，BCL6的表达还显著延长了培养中原代人B细胞的复制寿命，并诱导细胞周期蛋白D1的表达，这表明BCL6在淋巴细胞中具有类似的活性。我们的结果表明，BCL6通过使细胞对来自p19(ARF) - p53通路的抗增殖信号无反应而促进肿瘤发生。
Senescence limits the proliferative capacity of primary cells in culture. We describe here a genetic screen to identify genes that allow bypass of this checkpoint. Using retroviral cDNA expression libraries' we identify BCL6 as a potent inhibitor of senescence. BCL6 is frequently activated in non-Hodgkin's lymphoma, but its mechanism of action has remained unclear. BCL6 efficiently immortalizes primary mouse embryonic fibroblasts and cooperates with RAS in oncogenic transformation. BCL6 overrides the senescence response downstream of p53 through a process that requires induction of cyclin D1 expression, as cyclin D1 knockout fibroblasts are specifically resistant to BCL6 immortalization. We show that BCL6 expression also dramatically extends the replicative lifespan of primary human B cells in culture and induces cyclin D1 expression, indicating that BCL6 has a similar activity in lymphoid cells. Our results suggest that BCL6 contributes to oncogenesis by rendering cells unresponsive to antiproliferative signals from the p19(ARF)-p53 pathway.