Kimmel Cancer Center, Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America.
PLoS One. 2010 Jan 1;5(1):e8558. doi: 10.1371/journal.pone.0008558.
The RB and p53 tumor suppressors are mediators of DNA damage response, and compound inactivation of RB and p53 is a common occurrence in human cancers. Surprisingly, their cooperation in DNA damage signaling in relation to tumorigenesis and therapeutic response remains enigmatic. In the context of individuals with heritable retinoblastoma, there is a predilection for secondary tumor development, which has been associated with the use of radiation-therapy to treat the primary tumor. Furthermore, while germline mutations of the p53 gene are critical drivers for cancer predisposition syndromes, it is postulated that extrinsic stresses play a major role in promoting varying tumor spectrums and disease severities. In light of these studies, we examined the tumor suppressor functions of these proteins when challenged by exposure to therapeutic stress. To examine the cooperation of RB and p53 in tumorigenesis, and in response to therapy-induced DNA damage, a combination of genetic deletion and dominant negative strategies was employed. Results indicate that loss/inactivation of RB and p53 is not sufficient for cellular transformation. However, these proteins played distinct roles in response to therapy-induced DNA damage and subsequent tumorigenesis. Specifically, RB status was critical for cellular response to damage and senescence, irrespective of p53 function. Loss of RB resulted in a dramatic evolution of gene expression as a result of alterations in epigenetic programming. Critically, the observed changes in gene expression have been specifically associated with tumorigenesis, and RB-deficient, recurred cells displayed oncogenic characteristics, as well as increased resistance to subsequent challenge with discrete therapeutic agents. Taken together, these findings indicate that tumor suppressor functions of RB and p53 are particularly manifest when challenged by cellular stress. In the face of such challenge, RB is a critical suppressor of tumorigenesis beyond p53, and RB-deficiency could promote significant cellular evolution, ultimately contributing to a more aggressive disease.
RB 和 p53 肿瘤抑制因子是 DNA 损伤反应的介质，RB 和 p53 的复合失活在人类癌症中很常见。令人惊讶的是，它们在与肿瘤发生和治疗反应有关的 DNA 损伤信号中的合作仍然是一个谜。在遗传性视网膜母细胞瘤患者中，存在继发性肿瘤发展的倾向，这与使用放射疗法治疗原发性肿瘤有关。此外，虽然 p53 基因突变是癌症易感性综合征的关键驱动因素，但据推测，外在应激在促进不同的肿瘤谱和疾病严重程度方面起着主要作用。有鉴于此，我们研究了这些蛋白质在受到治疗应激时的肿瘤抑制功能。为了研究 RB 和 p53 在肿瘤发生中的合作以及对治疗诱导的 DNA 损伤的反应，我们采用了基因缺失和显性负突变策略的组合。结果表明，RB 和 p53 的缺失/失活不足以引起细胞转化。然而，这些蛋白质在治疗诱导的 DNA 损伤和随后的肿瘤发生中发挥了不同的作用。具体而言，RB 状态对于细胞对损伤和衰老的反应是至关重要的，而与 p53 功能无关。RB 的缺失导致表观遗传编程改变导致基因表达的急剧变化。至关重要的是，观察到的基因表达变化与肿瘤发生特异性相关，RB 缺陷、复发的细胞表现出致癌特征，并且对随后用离散治疗剂的挑战具有更高的抗性。总之，这些发现表明，RB 和 p53 的肿瘤抑制功能在受到细胞应激时特别明显。在面临这种挑战时，RB 是超越 p53 的肿瘤发生的关键抑制因子，RB 缺失可能促进显著的细胞进化，最终导致更具侵袭性的疾病。
