RB Restricts DNA Damage-Initiated Tumorigenesis through an LXCXE-Dependent Mechanism of Transcriptional Control
RB Restricts DNA Damage-Initiated Tumorigenesis through an LXCXE-Dependent Mechanism of Transcriptional Control
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DOI：
10.1016/j.molcel.2011.06.029
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发表时间：
2011-08-19
期刊：
影响因子：
16
通讯作者：
Knudsen, Erik S.
中科院分区：
文献类型：
--
作者：
Bourgo, Ryan J.;Thangavel, Chellappagounder;Knudsen, Erik S.
LXCXE肽基序促进RB肿瘤抑制因子与大量细胞蛋白之间的相互作用，这些蛋白预期会影响不同的生物过程。体外和体内分析表明，LXCXE的结合功能是RB启动子关联和基础基因表达的控制。依赖于这种功能的RB是揭露后DNA损伤，其中LXCXE的结合是必不可少的发挥控制E2F3和抑制细胞周期的进程中存在的遗传毒性应激。基因表达谱分析显示，RB的这一特定方面协调的转录程序与人类肝细胞癌的进展和不良的疾病结局相关。与这些发现一致，生物挑战揭示了在体内抑制遗传毒素引发的肝细胞癌中需要LXCXE结合。总之，这些研究建立了RB介导的转录控制，响应遗传毒性损伤，和肿瘤抑制的LXCXE结合基序的重要作用。
The LXCXE peptide motif facilitates interaction between the RB tumor suppressor and a large number of cellular proteins that are expected to impinge on diverse biological processes. In vitro and in vivo analyses demonstrated that LXCXE binding function is dispensable for RB promoter association and control of basal gene expression. Dependence on this function of RB is unmasked after DNA damage, wherein LXCXE binding is essential for exerting control over E2F3 and suppressing cell-cycle progression in the presence of genotoxic stress. Gene expression profiling revealed that the transcriptional program coordinated by this specific aspect of RB is associated with progression of human hepatocellular carcinoma and poor disease outcome. Consistent with these findings, biological challenge revealed a requirement for LXCXE binding in suppression of genotoxin-initiated hepatocellular carcinoma in vivo. Together, these studies establish an essential role of the LXCXE binding motif for RB-mediated transcriptional control, response to genotoxic insult, and tumor suppression.