Background Integrin-mediated adhesion is normally required for cytokinetic abscission, and failure in the process can generate potentially oncogenic tetraploid cells. Here, detachment-induced formation of oncogenic tetraploid cells was analyzed in non-transformed human BJ fibroblasts and BJ expressing SV40LT (BJ-LT) ± overactive HRas. Results In contrast to BJ and BJ-LT cells, non-adherent BJ-LT-Ras cells recruited ALIX and CHMP4B to the midbody and divided. In detached BJ and BJ-LT cells regression of the cytokinetic furrow was suppressed by intercellular bridge-associated septin; after re-adhesion these cells divided by cytofission, however, some cells became bi-nucleated because of septin reorganization and furrow regression. Adherent bi-nucleated BJ cells became senescent in G1 with p21 accumulation in the nucleus, apparently due to p53 activation since adherent bi-nucleated BJ-LT cells passed through next cell cycle and divided into mono-nucleated tetraploids; the two centrosomes present in bi-nucleated BJ cells fused after furrow regression, pointing to the PIDDosome pathway as a possible mechanism for the p53 activation. Conclusions Several mechanisms prevent detached normal cells from generating tumor-causing tetraploid cells unless they have a suppressed p53 response by viruses, mutation or inflammation. Importantly, activating Ras mutations promote colony growth of detached transformed cells by inducing anchorage-independent cytokinetic abscission in single cells.

中文翻译：

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Septin 和 Ras 调节分离细胞中的细胞因子脱落。

背景 细胞因子脱落通常需要整合素介导的粘附，并且该过程中的失败会产生潜在的致癌四倍体细胞。在这里，在未转化的人 BJ 成纤维细胞和 BJ 表达 SV40LT (BJ-LT) ± 过度活跃的 HRas 中分析了分离诱导的致癌四倍体细胞的形成。结果 与 BJ 和 BJ-LT 细胞相比，非贴壁 BJ-LT-Ras 细胞将 ALIX 和 CHMP4B 募集到中间体并分裂。在分离的 BJ 和 BJ-LT 细胞中，细胞间桥相关的脓毒症抑制了细胞因子沟的消退；然而，在重新粘附后，这些细胞因细胞分裂而分裂，但由于化脓蛋白重组和沟退化，一些细胞变成了双核细胞。贴壁的双核 BJ 细胞在 G1 期衰老，p21 在细胞核中积累，显然是由于 p53 激活，因为贴壁的双核 BJ-LT 细胞通过下一个细胞周期并分裂成单核四倍体；双核 BJ 细胞中存在的两个中心体在沟退化后融合，表明 PIDDosome 途径是 p53 激活的可能机制。结论 有几种机制可防止脱落的正常细胞产生导致肿瘤的四倍体细胞，除非它们因病毒、突变或炎症而抑制 p53 反应。重要的是，激活 Ras 突变通过诱导单细胞中不依赖锚定的细胞因子脱落来促进分离的转化细胞的集落生长。双核 BJ 细胞中存在的两个中心体在沟退化后融合，表明 PIDDosome 途径是 p53 激活的可能机制。结论 有几种机制可防止脱落的正常细胞产生导致肿瘤的四倍体细胞，除非它们因病毒、突变或炎症而抑制 p53 反应。重要的是，激活 Ras 突变通过诱导单细胞中不依赖锚定的细胞因子脱落来促进分离的转化细胞的集落生长。双核 BJ 细胞中存在的两个中心体在沟退化后融合，表明 PIDDosome 途径是 p53 激活的可能机制。结论 有几种机制可防止脱落的正常细胞产生导致肿瘤的四倍体细胞，除非它们因病毒、突变或炎症而抑制 p53 反应。重要的是，激活 Ras 突变通过诱导单细胞中不依赖锚定的细胞因子脱落来促进分离的转化细胞的集落生长。