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Role of the mitochondrial RNA polymerase POLRMT in MYC function

线粒体 RNA 聚合酶 POLRMT 在 MYC 功能中的作用

基本信息

批准号：
8187278
负责人：
STEVEN B. MCMAHON
金额：
$ 28.95万
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：
2011-08-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8187278
关键词：
Anabolism Apoptosis Apoptotic Biochemical Biogenesis Cancer cell line Cells Coupled DNA-Directed RNA Polymerase Data Data Set Dependence Electron Transport Enzymes Epithelial Event Exhibits Future Genes Genetic Genetic Transcription Glutamine Growth Human IMPDH1 gene IMPDH2 gene Image Inner mitochondrial membrane Intervention Knowledge Link Lymphoma Malignant - descriptor Malignant Neoplasms Mammary gland Mediating Messenger RNA Meta-Analysis Metabolic Metabolism Mitochondria Mitochondrial DNA Mitochondrial RNA Molecular Profiling Multiple Myeloma Normal Cell Nuclear Nuclear RNA Nucleotide Biosynthesis Oncogene Proteins Oxidoreductase Pathway interactions Play Protein Isoforms Proteins Pyrimidine RNA RNA primers Reaction Regulation Relative (related person)Residual state Ribosomal RNA Role Sampling Testing Therapeutic Intervention Thymidylate Synthase Transfer RNA Tumor Suppressor Proteins Uridine Work addiction base cancer cell cancer gene expression cancer therapy cell transformation enzyme pathway in vivo inhibitor/antagonist insight lactate dehydrogenase A leukemia/lymphoma melanoma mitochondrial genome neoplastic cell novel novel therapeutics optimism polypeptide pyrimidine metabolism research study therapeutic target trait tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Cancer cells exhibit profound metabolic differences from their normal counterpart. Currently, there is significant optimism that the metabolic traits unique to cancer cells may represent viable therapeutic targets. Work from a number of groups, ours included, has firmly implicated the MYC oncoprotein as a central regulator of the metabolic reprogramming that takes place in human cancer cells. To gain insight into MYC's role in human cancer, we recently performed an unbiased expression profiling screen to identify essential downstream targets whose transcription is tightly correlated with malignant transformation. Via the screen, we identified the POLRMT gene. POLRMT is a nuclear gene that encodes the single chain RNA polymerase molecule, mtRNAP that is responsible for transcription from the small, circular mitochondrial genome (mtDNA). (MYC had previously been shown to regulate the three major nuclear RNA polymerase molecules.) Functional studies of the induction of POLRMT/mtRNAP by MYC show that MYC regulates all transcription within the mitochondria via its control of POLRMT expression. Furthermore, because mtRNAP transcribes the RNA primers required for replication of the mtDNA, MYC regulates cellular mitochondrial genome content as well. Genetic rescue experiments show that both of these efects depends exclusively on mtRNAP and not on a recently described nuclear isoform encoded by POLRMT, spRNAP-IV. The link between MYC and POLRMT expression has been confirmed in a variety of human cancer cell lines and is supported by evidence from public cancer gene expression datasets. MYC also regulates POLRMT expression in primary human cells. Most importantly, blocking the ability of MYC to induce POLRMT expression results in robust apoptosis that strictly depends on the presence of activated MYC. Strategies that reactivate the latent apoptotic potential or "intrinsic tumor suppressor activity" of MYC are widely viewed as an exciting opportunity for future anti-cancer therapy. Finally, the MYC-dependent apoptosis that results from blocking POLRMT induction appears to result from a unique requirement for POLRMT/mtRNAP in the expression of mitochondrial-encoded components of the electron transport chain and subsequent effects on the pyrimidine biosynthesis pathway. Targeting pyrimidine biosynthesis has been recognized as a successful anti-cancer therapy for many decades and our data suggest that induction of POLRMT/mtRNAP may represent a novel node for intervention in this pathway, specifically in the forms of human cancer that express high levels of MYC. The studies proposed here will test this hypothesis and provide a detailed mechanistic understanding of the pathway we have identified, along with the essential, MYC-dependent survival function it provides to tumor cells. PUBLIC HEALTH RELEVANCE: Cancer cells have a unique set of metabolic reactions relative to their normal counterparts and many current efforts are focused on exploiting these differences for anti-cancer therapy. We have identified a unique mitochondrial enzyme regulated by the MYC oncoprotein that is essential for survival of cancer cells and which represents a targetable node in the pathway MYC controls.

描述（由申请人提供）：癌细胞与正常细胞表现出深刻的代谢差异。目前，人们非常乐观地认为，癌细胞特有的代谢特征可能代表可行的治疗靶点。包括我们在内的许多研究小组的工作已经明确地表明，MYC癌蛋白是人类癌细胞中发生的代谢重编程的中心调节因子。为了深入了解MYC在人类癌症中的作用，我们最近进行了一项无偏倚的表达谱筛选，以确定转录与恶性转化密切相关的重要下游靶点。通过筛选，我们确定了POLRMT基因。POLRMT是一种编码单链RNA聚合酶分子mtRNAP的核基因，该分子负责从小的圆形线粒体基因组（mtDNA）转录。（MYC先前已被证明可以调节三种主要的核RNA聚合酶分子。）对MYC诱导POLRMT/mtRNAP的功能研究表明，MYC通过控制POLRMT表达来调节线粒体内的所有转录。此外，由于mtRNAP转录mtDNA复制所需的RNA引物，MYC也调节细胞线粒体基因组的含量。遗传拯救实验表明，这两种作用完全依赖于mtRNAP，而不是最近描述的由POLRMT编码的核异构体spRNAP-IV。MYC和POLRMT表达之间的联系已在多种人类癌细胞系中得到证实，并得到公共癌症基因表达数据集证据的支持。MYC也调节人原代细胞中POLRMT的表达。最重要的是，阻断MYC诱导POLRMT表达的能力会导致强烈的凋亡，这种凋亡严格依赖于活化的MYC的存在。重新激活MYC的潜在凋亡潜能或“内在肿瘤抑制活性”的策略被广泛认为是未来抗癌治疗的一个令人兴奋的机会。最后，阻断POLRMT诱导导致的myc依赖性凋亡似乎是由于POLRMT/mtRNAP在电子传递链中线粒体编码组分的表达和随后对嘧啶生物合成途径的影响中对POLRMT/mtRNAP的独特要求。几十年来，靶向嘧啶生物合成已被认为是一种成功的抗癌治疗方法，我们的数据表明，诱导POLRMT/mtRNAP可能代表了干预这一途径的新节点，特别是在表达高水平MYC的人类癌症形式中。这里提出的研究将验证这一假设，并提供我们已经确定的途径的详细机制理解，以及它为肿瘤细胞提供的基本的myc依赖性生存功能。