The RASSF1A isoform of RASSF1 promotes microtubule stability and suppresses tumorigenesis
The RASSF1A isoform of RASSF1 promotes microtubule stability and suppresses tumorigenesis
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DOI：
10.1128/mcb.25.18.8356-8367.2005
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发表时间：
2005-09-01
影响因子：
5.3
通讯作者：
Bradley, A
中科院分区：
文献类型：
--
作者：
van der Weyden, L;Tachibana, KK;Bradley, A
RASSF1 的 RASSF1A 亚型经常因人类癌症中的表观遗传改变而失活，但目前尚不清楚它是否以及如何发挥肿瘤抑制因子的作用。 RASSF1A 过度表达可减少体外集落形成和体内癌细胞系的致瘤性。相反，RASSF1A 敲低会导致多种有丝分裂缺陷，从而可能促进基因组不稳定。在这里，我们使用遗传方法通过在小鼠中定向删除 Rassf1A 来解决 RASSF1A 作为体内肿瘤抑制因子的功能。 Rassf1A 缺失小鼠存活且具有生育能力，并且没有表现出病理异常。 Rassf1A 缺失的胚胎成纤维细胞表现出对微管解聚剂的敏感性增加。在 Rassf1A 无效成纤维细胞中未检测到明显改变的细胞周期参数或中心体数量畸变。 Rassf1A无效的成纤维细胞并未表现出对微管毒物或DNA损伤剂的敏感性增加，并且没有表现出总体基因组不稳定性的证据，这表明细胞对基因毒素的反应不受影响。与野生型小鼠相比，Rassf1A 缺失小鼠的自发肿瘤发生率增加，存活率降低。与野生型小鼠相比，受辐射的 Rassf1A 缺失小鼠也表现出肿瘤易感性增加，特别是与胃肠道相关的肿瘤。因此，我们的结果证明 Rassf1A 作为肿瘤抑制基因。
The RASSF1A isoform of RASSF1 is frequently inactivated by epigenetic alterations in human cancers, but it remains unclear if and how it acts as a tumor suppressor. RASSF1A overexpression reduces in vitro colony formation and the tumorigenicity of cancer cell lines in vivo. Conversely, RASSF1A knockdown causes multiple mitotic defects that may promote genomic instability. Here, we have used a genetic approach to address the function of RASSF1A as a tumor suppressor in vivo by targeted deletion of Rassf1A in the mouse. Rassf1A null mice were viable and fertile and displayed no pathological abnormalities. Rassf1A null embryonic fibroblasts displayed an increased sensitivity to microtubule depolymerizing agents. No overtly altered cell cycle parameters or aberrations in centrosome number were detected in Rassf1A null fibroblasts. Rassf1A null fibroblasts did not show increased sensitivity to microtubule poisons or DNA-damaging agents and showed no evidence of gross genomic instability, suggesting that cellular responses to genotoxins were unaffected. Rassf1A null mice showed an increased incidence of spontaneous tumorigenesis and decreased survival rate compared with wild-type mice. Irradiated Rassf1A null mice also showed increased tumor susceptibility, particularly to tumors associated with the gastrointestinal tract, compared with wild-type mice. Thus, our results demonstrate that Rassf1A acts as a tumor suppressor gene.