RB depletion is required for the continuous growth of tumors initiated by loss of RB.
RB depletion is required for the continuous growth of tumors initiated by loss of RB.
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DOI：
10.1371/journal.pgen.1009941
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发表时间：
2021-12
期刊：
影响因子：
4.5
通讯作者：
Sage J
中科院分区：
文献类型：
--
作者：
Doan A;Arand J;Gong D;Drainas AP;Shue YT;Lee MC;Zhang S;Walter DM;Chaikovsky AC;Feldser DM;Vogel H;Dow LE;Skotheim JM;Sage J
视网膜母细胞瘤(RB)肿瘤抑制因子在许多人类肿瘤中功能失活，这种失活在一定程度上通过允许不受控制的增殖促进肿瘤的发生。Rb已经得到了广泛的研究，但它在正常细胞和癌细胞中的作用机制仍然只有部分了解。在这里，我们描述了一种新的小鼠模型来研究Rb耗竭及其在体内重新激活的后果。在这些小鼠中，针对Rb基因敲除的shRNA分子的诱导导致了类似Rb基因敲除小鼠的表型发展，包括垂体和甲状腺肿瘤的发展。Rb的重新表达导致癌细胞周期停滞，并抑制由E2F活性驱动的转录程序。因此，Rb的持续丢失是维持肿瘤表型所必需的，这种新的小鼠模型将为研究Rb在体内的功能提供一个新的平台。视网膜母细胞瘤蛋白(Rb)是细胞周期的中央调节因子。Rb的功能失活会导致不受控制的增殖，在人类癌症中经常发生。临床前模型的实验已经清楚地证明，Rb的丢失是癌症发展的强大推动者。然而，RB执行其肿瘤抑制功能的机制仍只有部分了解。在这里，我们描述了一种新的基因工程小鼠模型，在该模型中，Rb的表达可以打开或关闭。利用这个可控的Rb基因敲除系统，我们研究了Rb在正常细胞中丢失和在癌细胞中重新表达的后果。我们发现，小鼠长期的Rb基因敲除会导致垂体和甲状腺肿瘤的发展，概括了以前报道的Rb基因敲除小鼠的表型，从而验证了这个新的小鼠模型。值得注意的是，由于Rb的缺失，Rb在垂体肿瘤中的重新表达足以阻止肿瘤的生长，这表明这些肿瘤仍然依赖Rb的缺失来扩大。
The retinoblastoma (RB) tumor suppressor is functionally inactivated in a wide range of human tumors where this inactivation promotes tumorigenesis in part by allowing uncontrolled proliferation. RB has been extensively studied, but its mechanisms of action in normal and cancer cells remain only partly understood. Here, we describe a new mouse model to investigate the consequences of RB depletion and its re-activation in vivo. In these mice, induction of shRNA molecules targeting RB for knock-down results in the development of phenotypes similar to Rb knock-out mice, including the development of pituitary and thyroid tumors. Re-expression of RB leads to cell cycle arrest in cancer cells and repression of transcriptional programs driven by E2F activity. Thus, continuous RB loss is required for the maintenance of tumor phenotypes initiated by loss of RB, and this new mouse model will provide a new platform to investigate RB function in vivo. The retinoblastoma protein (RB) is a central regulator of the cell cycle. Functional inactivation of RB leads to unchecked proliferation and is a frequent occurrence in human cancer. Experiments with pre-clinical models have clearly demonstrated that loss of RB is a strong promoter of cancer development. However, the mechanisms through which RB carries out its tumor suppressor function remain only partly understood. Here, we describe a new genetically engineered mouse model in which RB expression can be turned on or off. Using this controllable RB knock-down system, we investigated both the consequences of RB loss in normal cells and its re-expression in cancer cells. We found that long-term RB knock-down in mice leads to the development of pituitary and thyroid tumors, recapitulating previously reported phenotypes of Rb knockout mice, thus validating this new mouse model. Notably, re-expression of RB in pituitary tumors initiated by loss of RB was sufficient to block tumor growth, indicating that these tumors are still dependent on RB loss for their expansion.
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影响因子：
24.5
作者：
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作者：
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影响因子：
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作者：
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