London Regional Cancer Program, Western University, London, Ontario, Canada.
PLoS One. 2013 Aug 6;8(8):e72236. doi: 10.1371/journal.pone.0072236. Print 2013.
The Retinoblastoma protein (pRB) is a key tumor suppressor that is functionally inactivated in most cancers. pRB regulates the cell division cycle and cell cycle exit through protein-protein interactions mediated by its multiple binding interfaces. The LXCXE binding cleft region of pRB mediates interactions with cellular proteins that have chromatin regulatory functions. Chromatin regulation mediated by pRB is required for a stress responsive cell cycle arrest, including oncogene induced senescence. The in vivo role of chromatin regulation by pRB during senescence, and its relevance to cancer is not clear.
METHODOLOGY/PRINCIPAL FINDINGS: Using gene-targeted mice, uniquely defective for pRB mediated chromatin regulation, we investigated its role during transformation and tumor progression in response to activation of oncogenic ras. We report that the pRB(∆L) mutation confers susceptibility to escape from HrasV12 induced senescence and allows transformation in vitro, although these cells possess high levels of DNA damage. Intriguingly, LSL-Kras, Rb1 (∆L/∆L) mice show delayed lung tumor formation compared to controls. This is likely due to the increased apoptosis seen in the early hyperplastic lesions shortly following ras activation that inhibits tumor progression. Furthermore, DMBA treatment to induce sporadic ras mutations in other tissues also failed to reveal greater susceptibility to cancer in Rb1 (∆L/∆L) mice.
CONCLUSIONS/SIGNIFICANCE: Our data suggests that chromatin regulation by pRB can function to limit proliferation, but its loss fails to contribute to cancer susceptibility in ras driven tumor models because of elevated levels of DNA damage and apoptosis.
视网膜母细胞瘤蛋白（pRB）是一种关键的肿瘤抑制因子，在大多数癌症中功能失活。pRB 通过其多个结合界面介导的蛋白质-蛋白质相互作用来调节细胞分裂周期和细胞周期退出。pRB 的 LXCXE 结合裂缝区域介导与具有染色质调节功能的细胞蛋白的相互作用。pRB 介导的染色质调节对于应激反应性细胞周期停滞是必需的，包括癌基因诱导的衰老。pRB 在衰老过程中对染色质调节的体内作用及其与癌症的相关性尚不清楚。
方法/主要发现：使用基因靶向小鼠，其 pRB 介导的染色质调节有独特缺陷，我们研究了其在致癌 ras 激活时转化和肿瘤进展过程中的作用。我们报告称，pRB(∆L)突变赋予了逃避 HrasV12 诱导衰老的易感性，并允许体外转化，尽管这些细胞具有高水平的 DNA 损伤。有趣的是，LSL-Kras，Rb1(∆L/∆L) 小鼠与对照相比显示出延迟的肺肿瘤形成。这可能是由于 ras 激活后不久在早期增生性病变中观察到的增加的细胞凋亡，这抑制了肿瘤进展。此外，用 DMBA 处理以诱导其他组织中的散发性 ras 突变也未能揭示 Rb1(∆L/∆L) 小鼠对癌症的更高易感性。
结论/意义：我们的数据表明，pRB 的染色质调节可以起到限制增殖的作用，但其缺失并未导致 ras 驱动的肿瘤模型中癌症易感性增加，因为高水平的 DNA 损伤和细胞凋亡。
