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

新型 MYC/BCL2 通路在细胞凋亡和转化中的作用

基本信息

批准号：
8119808
负责人：
STEVEN B. MCMAHON
金额：
$ 20.21万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-04 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8119808
关键词：
Affect Animal Model Apoptosis Apoptotic BCL-2 Protein BCL2 gene Binding Biochemical Cancer Patient Cell Cycle Progression Cell Death Cell Survival Cells Cessation of life Clinical Complex Coupled Cultured Cells Data Decision Making Disease Progression Equilibrium Event Exhibits Future Genetic Genetic Transcription Goals Growth Growth Factor Human Hypoxia In Vitro Link Malignant - descriptor Malignant Neoplasms Mediating Mitochondria Mitochondrial Proteins Morphology Mus Normal Cell Nuclear Proteins Oncogene Proteins Oncogenes Organism Outer Mitochondrial Membrane Pathway interactions Play Point Mutation Process Property Protein Family Proteins Role Series Signal Transduction Stimulus Testing Therapeutic Therapeutic Index Transcription Repressor/Corepressor Transcriptional Regulation Tumor Suppression ZNF151 gene accomplished suicide base cancer cell cancer therapy cell transformation deprivation in vivo inhibitor/antagonist neoplastic cell new therapeutic target novel overexpression preclinical study response small hairpin RNA small molecule therapeutic development transcription factor tumor tumorigenesis

项目摘要

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.

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。矛盾的是，MYC 驱动细胞周期进程的能力与同样有效的诱导细胞凋亡的能力相匹配。决定 MYC 是否驱动增殖或凋亡的生化信号仍知之甚少。然而，特异性激活 MYC 潜在细胞凋亡潜力的能力（也称为“内在肿瘤抑制活性”）被广泛认为是一个有吸引力的治疗目标。从各种人类和小鼠遗传学研究中可以清楚地看出，促生存 BCL2 蛋白在阻断 MYC 内在肿瘤抑制活性中发挥着关键作用。我们已经确定了 BCL2 通路中受 MYC 控制的生化事件，这些事件对于肿瘤细胞存活和凋亡的决定至关重要。这一进展基于我们对 MYC、MIZ1 转录因子和 BCL2 基因座转录之间联系的鉴定。 MIZ1 通常激活 BCL2 转录，而 MYC 在诱导细胞凋亡时阻断这种激活。很明显，该途径在肿瘤细胞中必定受到损害，因为肿瘤细胞不会响应 MYC 过度表达而表现出自发性凋亡。值得注意的是，我们已经证明，通过使用小分子抑制 BCL2 或通过 shRNA 介导的耗竭来模拟该途径的重新激活，可以完全恢复细胞凋亡功能。因此，更深入地了解构成该途径的生化事件可能有助于确定治疗策略的目标点（目标 1）。如果要通过 MYC 中这个先前未被识别的单个节点的功能性失活来选择性触发过表达 MYC 的人类肿瘤经历细胞凋亡，我们必须使用动物模型测试这一新途径是否在体内调节肿瘤中 MYC 活性中发挥作用（目的2）。公共健康相关性：正常人类细胞含有一种途径，当它们不恰当地表达癌基因时，会导致它们自杀（或凋亡）。我们已经确定了该通路如何响应最常见的人类癌基因 MYC 发挥作用，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通路。