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

• 批准号: 8236880
• 负责人: STEVEN B. MCMAHON
• 金额: $ 16.86万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-04 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236880
• 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; public health relevance; response; small hairpin RNA; small molecule; therapeutic development; transcription factor; tumor; tumorigenesis

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(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强大的诱导凋亡能力相匹配。决定MYC是促进增殖还是导致细胞凋亡的生化信号仍然知之甚少。然而，能够特异性地激活MYC的潜在凋亡潜能(也被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。从人类和小鼠的各种遗传学研究中可以清楚地看出，促进生存的bcl2蛋白在阻断MYC固有的肿瘤抑制活性方面发挥着关键作用。我们已经确定了BCL2通路中由MYC控制的生化事件，这些事件对于在肿瘤细胞存活和凋亡之间做出决定是至关重要的。这一进展是基于我们发现了MYC、MIZ1转录因子和BCL2基因座转录之间的联系。MIZ1通常激活BCL2转录，而MYC在诱导细胞凋亡时阻止这种激活。显然，这一途径在肿瘤细胞中必须受到影响，因为它们不会对MYC的过度表达产生自发的凋亡反应。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介导的耗尽来模拟这一途径的重新激活，完全恢复了凋亡功能。因此，更深入地了解构成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)。如果过度表达MYC的人类肿瘤要通过MYC中这个单一的、以前未被识别的节点的功能失活来选择性地触发细胞凋亡，我们必须使用动物模型在体内测试这一新途径是否在调节肿瘤中的MYC活性方面发挥作用(目标2)。 与公共卫生相关：正常的人类细胞包含一条途径，当它们不适当地表达癌基因时，会导致它们自杀(或凋亡)。我们已经确定了该途径是如何响应最常见的人类癌基因myc的功能的，目前的努力旨在了解是否可以特异性地针对癌细胞来激活细胞死亡途径。