p53-GAMT pathway in cancer cell metabolism and DNA damage-induced carcinogenesis

p53-GAMT 通路在癌细胞代谢和 DNA 损伤诱发癌变中的作用

基本信息

批准号：
8629620
负责人：
SAM W LEE
金额：
$ 32.77万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-13 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8629620
关键词：
Anabolism Apoptosis Autophagocytosis Cancer Biology Cancer Etiology Cell Death Cell Survival Cell physiology Cells Cellular Stress Response Cessation of life Characteristics Consumption Creatine DNA Damage Decision Making Development Energy Metabolism Energy-Generating Resources Enzymes Exposure to Gene Targeting Genotoxic Stress Glucose Glycolysis Goals Guanidinoacetate N-Methyltransferase Homeostasis Knockout Mice Link Malignant - descriptor Malignant Neoplasms Mediating Metabolic Metabolic stress Metabolism Mitochondria Nutrient Oxygen Consumption Pathway interactions Play Process Production Protein p53 Recovery Regulation Respiration Role Signal Transduction Starvation Stress Tissues Tumor Suppressor Proteins Up-Regulation Warburg Effect base biological adaptation to stress cancer cell carcinogenesis conventional therapy deprivation fatty acid oxidation gene function glucose metabolism in vivo novel public health relevance response tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Cancer cells have enhanced glycolysis and show lower oxygen consumption, indicating a shift to glycolysis for the production of energy, thereby contributing to the metabolic change known as Warburg effect, which is characteristic of virtually all cancers. Many mysteries remain unsolved in our understanding of cancer cell metabolism. Recent discoveries indicate that tumor suppressor p53 has much broader cellular functions, such as regulating glucose metabolism and mitochondrial respiration. We identified GAMT/guanidinoacetate methyltransferase, an enzyme involved in creatine synthesis metabolism as a novel p53 target gene, and a key downstream effector of the adaptive response to DNA damage and nutrient stress in cancer cels. We reveal that GAMT is involved in p53-dependent apoptosis in response to DNA damage/genotoxic stress, and also demonstrate that the GAMT pathway plays an essential role in the regulation of ATP homeostasis during nutrient stress. Surprisingly, we also found that p53->GAMT up-regulates fatty acid oxidation (FAO) induced by DNA damage stress or glucose starvation, facilitating the use of this pathway as an alternative ATP-generating energy source when glucose is scarce. The main goal of this application is to understand the underlying mechanisms for the unusual effect of the p53-GAMT-Creatine pathway in DNA damage-mediated carcinogenesis, as well as in cancer cell metabolism. The specific aims are to (1) investigate the underlying mechanism(s) for the substitutive effects of the p53-GAMT-Creatine pathway in energy metabolism in cancer cells; (2) define the role of this pathway in regulating DNA damage responses (cell fate decision; cell death or survival) in cancer cells; and (3) determine the function of GAMT in metabolic and DNA damage stress responses using mouse knock-out approaches. Our findings of the p53->GAMT-Creatine pathway represent a new link between cellular stress responses and the metabolic processes of creatine synthesis and FAO, providing implications for understanding selective nutrient adaptation and how this might impact cancer development and responses to conventional therapies. The proposed studies are highly relevant for cancer biology, as they will reveal how metabolic changes impact cancer and how this newly discovered pathway is emerging as a key contributor to tumorigenesis/carcinogenesis.

描述（由申请人提供）：癌细胞的糖酵解增强，耗氧量降低，表明其转变为糖酵解来产生能量，从而导致被称为瓦伯格效应的代谢变化，这几乎是所有癌症的特征。我们对癌细胞代谢的理解仍有许多未解之谜。最近的发现表明肿瘤抑制因子 p53 具有更广泛的细胞功能，例如调节葡萄糖代谢和线粒体呼吸。我们确定了 GAMT/胍基乙酸甲基转移酶（一种参与肌酸合成代谢的酶）作为一种新型 p53 靶基因，并且是癌细胞对 DNA 损伤和营养应激的适应性反应的关键下游效应子。我们揭示了 GAMT 参与响应 DNA 损伤/基因毒性应激的 p53 依赖性细胞凋亡，并且还证明 GAMT 途径在营养应激期间的 ATP 稳态调节中发挥重要作用。令人惊讶的是，我们还发现 p53->GAMT 上调由 DNA 损伤应激或葡萄糖饥饿诱导的脂肪酸氧化 (FAO)，从而促进在葡萄糖稀缺时使用该途径作为替代的 ATP 生成能源。该应用的主要目标是了解 p53-GAMT-肌酸途径在 DNA 损伤介导的致癌作用以及癌细胞代谢中的异常作用的潜在机制。具体目标是（1）研究p53-GAMT-肌酸通路在癌细胞能量代谢中的替代作用的潜在机制； (2) 定义该通路在调节癌细胞DNA损伤反应（细胞命运决定；细胞死亡或存活）中的作用； (3) 使用小鼠敲除方法确定 GAMT 在代谢和 DNA 损伤应激反应中的功能。我们对p53->GAMT-肌酸途径的发现代表了细胞应激反应与肌酸合成和FAO的代谢过程之间的新联系，为理解选择性营养适应以及这如何影响癌症的发展和对传统疗法的反应提供了启示。拟议的研究与癌症生物学高度相关，因为它们将揭示代谢变化如何影响癌症，以及这一新发现的途径如何成为肿瘤发生/癌变的关键因素。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A distinct role for Pin1 in the induction and maintenance of pluripotency.

Pin1 在多能性的诱导和维持中发挥着独特的作用。

DOI：
发表时间：
2011-04-01
期刊：
影响因子：
0
作者：
Nishi, Mayuko;Akutsu, Hidenori;Masui, Shinji;Kondo, Asami;Nagashima, Yoji;Kimura, Hirokazu;Perrem, Kilian;Shigeri, Yasushi;Toyoda, Masashi;Okayama, Akiko;Hirano, Hisashi;Umezawa, Akihiro;Yamamoto, Naoki;Lee, Sam W;Ryo, Akihide
通讯作者：
Ryo, Akihide

GAMT joins the p53 network: branching into metabolism.

GAMT 加入 p53 网络：分支进入新陈代谢。