Role of a novel MYC/BCL2 pathway in apoptosis and transformation

描述（由申请人提供）：MYC癌蛋白的异常表达是人类癌症中最常见的致病事件之一。有趣的是，MYC驱动细胞周期进程的能力与诱导细胞凋亡的同等有效能力相匹配。决定MYC是否驱动增殖或凋亡的生化信号仍然知之甚少。然而，特异性激活MYC的潜在凋亡潜能（也称为“内在肿瘤抑制活性”）的能力被广泛认为是有吸引力的治疗目标。从各种人类和小鼠遗传研究中清楚地看出，促存活BCL 2蛋白在阻断MYC的内在肿瘤抑制活性中起关键作用。我们已经确定了由MYC控制的BCL 2通路中的生化事件，并且这些事件对于在肿瘤细胞存活和凋亡之间做出决定至关重要。这一进展是基于我们对MYC、MIZ1转录因子和BCL 2基因座转录之间联系的鉴定。MIZ1通常激活BCL 2转录，MYC在诱导细胞凋亡时阻断这种激活。很明显，这种途径必须在肿瘤细胞中受到损害，因为它们不表现出响应于MYC过表达的自发凋亡。值得注意的是，我们已经表明，通过使用小分子抑制BCL 2或通过shRNA介导的耗竭来模拟该途径的再激活，可以完全恢复凋亡功能。因此，更深入地了解包括这一途径的生化事件可能有助于确定治疗策略可能针对的点（目标1）。 如果要选择性地触发过表达MYC的人类肿瘤通过MYC中这个单一的、以前未被识别的节点的功能失活来进行凋亡，我们必须使用动物模型测试这种新途径是否在体内调节肿瘤中的MYC活性中起作用（Aim 2）。 公共卫生相关性：正常的人类细胞含有一条通路，当它们不适当地表达致癌基因时，该通路会导致它们自杀（或凋亡）。我们已经确定了这种途径如何响应最常见的人类致癌基因MYC，目前的努力旨在了解癌细胞是否可以特异性靶向激活细胞死亡途径。

DESCRIPTION (provided by applicant): Aberrant expression of the MYC oncoprotein is among the most common causative events in human cancer. Paradoxically, the ability of MYC to drive cell cycle progression is matched by an equally potent capacity for inducing apoptosis. The biochemical signals that dictate whether MYC drives proliferation or apoptosis remain poorly understood. However, the ability to specifically activate MYC's latent apoptotic potential, (also referred to as "intrinsic tumor suppression activity"), is widely regarded as an attractive therapeutic goal. It is clear from a variety of human and mouse genetic studies that the pro- survival BCL2 protein plays a critical role in blocking MYC's intrinsic tumor suppression activity. We have identified biochemical events in the BCL2 pathway that are controlled by MYC, and which are critical for making the decision between tumor cell survival and apoptosis. This advance is based on our identification of the link between MYC, the MIZ1 transcription factor and the transcription of the BCL2 locus. MIZ1 normally activates BCL2 transcription and MYC blocks this activation when inducing apoptosis. It is clear that this pathway must be compromised in tumor cells since they do not exhibit spontaneous apoptosis in response to MYC overexpression. Notably, we have shown that mimicking the reactivation of this pathway by using small molecules to inhibit BCL2 or by shRNA-mediated depletion, completely restores apoptotic function. A deeper understanding of the biochemical events that comprise this pathway may thus help identify points at which therapeutic strategies might be aimed (Aim 1). If human tumors overexpressing MYC are to be selectively triggered to undergo apoptosis via functional inactivation of this single, previously unrecognized node in the MYC, we must test whether this new pathway plays a role in modulating MYC activity in tumors in vivo using animal models (Aim 2). PUBLIC HEALTH RELEVANCE: Normal human cells contain a pathway that causes them to commit suicide (or apoptosis) when they inappropriately express an oncogene. We have identified how this pathway functions in response to the most common human oncogene, MYC and current efforts are aimed at understanding whether cancer cells can be specifically targeted to activate the cell death pathway.