The RUNX Genes as Conditional Oncogenes: Insights from Retroviral Targeting and Mouse Models
The RUNX Genes as Conditional Oncogenes: Insights from Retroviral Targeting and Mouse Models
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DOI：
10.1007/978-981-10-3233-2_16
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发表时间：
2017-01-01
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影响因子：
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通讯作者：
Kilbey, Anna
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文献类型：
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作者：
Neil, James C.;Gilroy, Kathryn;Kilbey, Anna
观察到Runx基因作为逆转录病毒插入转录激活的靶标，确定了一个新的显性癌基因家族。然而，现在清楚的是，Runx基因是“条件性”癌基因，其过表达是生长抑制性的，除非伴随另一事件，如伴随的MYC过表达或p53功能丧失。值得注意的是，虽然MYC或RUNX过表达的致癌活性在p53完整时受到抑制，但两者的组合通过迄今未知的机制在体内中和了p53肿瘤抑制。此外，有新的证据表明，内源性的基础RUNX活性对维持MYC驱动的淋巴瘤细胞的活力和增殖是重要的。还有越来越多的证据表明，人类RUNX基因发挥类似的条件致癌作用，并被选择在多种类型的终末期癌症中过度表达。特别是，降低的RUNX活性也可能倾向于细胞永生化和转化，特别是通过突变型Ras。这些明显相互矛盾的观察结果可能在RUNX参与癌症的阶段特异性模型中得到调和。一个尚未完全解决的问题是三个Runx基因在癌症促进和抑制中功能冗余的程度。
The observation that the Runx genes act as targets for transcriptional activation by retroviral insertion identified a new family of dominant oncogenes. However, it is now clear that Runx genes are 'conditional' oncogenes whose over-expression is growth inhibitory unless accompanied by another event such as concomitant over-expression of MYC or loss of p53 function. Remarkably, while the oncogenic activities of either MYC or RUNX over-expression are suppressed while p53 is intact, the combination of both neutralises p53 tumour suppression in vivo by as yet unknown mechanisms. Moreover, there is emerging evidence that endogenous, basal RUNX activity is important to maintain the viability and proliferation of MYC-driven lymphoma cells. There is also growing evidence that the human RUNX genes play a similar conditional oncogenic role and are selected for over-expression in endstage cancers of multiple types. Paradoxically, reduced RUNX activity can also predispose to cell immortalisation and transformation, particularly by mutant Ras. These apparently conflicting observations may be reconciled in a stage-specific model of RUNX involvement in cancer. A question that has yet to be fully addressed is the extent to which the three Runx genes are functionally redundant in cancer promotion and suppression.