Whole chromosome instability resulting from the synergistic effects of pRB and p53 inactivation.
Whole chromosome instability resulting from the synergistic effects of pRB and p53 inactivation.
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全染色体不稳定性(CIN)是肿瘤细胞的共同特征，与肿瘤的进化和转移增加有关。一些研究表明，pRb抑癌基因的缺失会导致有丝分裂缺陷和染色体错误分离。PRb在许多类型的癌症中失活，这增加了pRb丢失可能是肿瘤中ICN的一般原因的可能性。矛盾的是，视网膜母细胞瘤肿瘤细胞具有相对稳定的核型，目前在人类癌症中PRB失活导致CIN的情况尚不清楚。在这里，我们利用基于FISH的方法来评分染色体拷贝数的数值异质性作为CIN的读数。使用这项技术，我们证明了高水平的CIN与联合失活的pRb和p53相关，并且这种关联在两个独立的癌细胞系中很明显。视网膜母细胞瘤细胞系具有保留野生型p53基因的特点，这为测试这种功能关系的相关性提供了机会。我们发现，视网膜母细胞瘤细胞系表现出当未转化细胞中的pRb被耗尽时所看到的有丝分裂缺陷，但野生型p53的存在抑制了非整倍体细胞的积累。在HCT116细胞中，pRb和p53失活之间也有类似的协同作用。这些结果表明，pRb的缺失促进了分离错误，而p53的缺失允许由此产生的、基因不稳定的癌细胞的耐受和持续增殖。因此，正是pRb和p53抑癌通路失活的协同作用促进了CIN的发生。
Whole chromosome instability (CIN) is a common feature of cancer cells and has been linked to increased tumor evolution and metastasis. Several studies have shown that the loss of the pRB tumor suppressor causes mitotic defects and chromosome missegregation. pRB is inactivated in many types of cancer and this raises rhe possibility that the ;loss of pRB may be ageneral cause of ICN in tumors. Paradoxically, retinoblastoma tumor cells have a relatively stable karyotype and currently the circumstances in which pRB inactivation causes CIN in human cancers are unclear. Here we utilize a FISH-based approach to score numerical heterogenity in chromosome copy number as a readout of CIN. Using this technique, we show that combined high levels of CIN correlate with the combined inactivation of pRB and p53 and that this association is evident in two independent panels of cancer cell lines. Retinoblastoma cell lines characteristically retain a wild-type p53 gene, providing an opportunity to test the relevance of this functional relationship. We show that retinoblastoma cell lines display the mitotic defects seen when pRB is depleted from non-transformed cells but that the presence of wild type p53 suppresses the accumulation of aneuploid cells. A similar synergy between pRB and p53 inactivation was observed in HCT116 cells. These results suggest that the loss of pRB promotes segregation errors while loss of p53 allows tolerance and continued proliferation of the resulting, genomically unstable cancer cells. Hence it is the cooperative effect of inactivation both pRB and p53 tumor suppressor pathways that promotes CIN.
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