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p53-Independent Cell Death Signaling by Mitomycin DNA Adducts

丝裂霉素 DNA 加合物的 p53 独立细胞死亡信号传导

基本信息

批准号：
8113210
负责人：
Jill E. Bargonetti
金额：
$ 29.49万
依托单位：
HUNTER COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-06 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8113210
关键词：
Address Alkylating Agents Antibodies Antineoplastic Agents Apoptotic Attention Autophagocytosis Binding Biological Models Caenorhabditis elegans Cancer cell line Cell Culture Techniques Cell Death Cell Death Signaling Process Cell Line Cells Cessation of life Complex DNA DNA Adducts DNA Damage DNA Repair DNA repair protein Dependency Development Drug Delivery Systems Drug Design Funding Genes Genetic Genotype Germ Cells Goals Hereditary Disease Homologous Gene Human Human Cell Line In Vitro Knock-out Knowledge Laboratories Laboratory Research Lesion Longevity Malignant Neoplasms Mediating Meiosis Methods Mitomycins Mitotic Modeling Mutation Necrosis Nematoda Nuclear Protein Nucleosides Oligonucleotides Other Genetics Outcome Pathway interactions Patients Pharmaceutical Preparations Phenotype Phosphorylation Phosphotransferases Play Positioning Attribute Pre-Clinical Model Protein p53 Proteins Publishing RNA Interference Recruitment Activity Signal Pathway Signal Transduction Signal Transduction Pathway Site Staging System TP53 gene Tissue Model Work adduct cancer cell cancer therapy cell killing chromatin immunoprecipitation colon cancer cell line comparative cytotoxicity design drug development in vivo independency innovation model development mutant plasmid DNA protein expression public health relevance research study sensor stereochemistry tumor

项目摘要

DESCRIPTION (provided by applicant): The need to identify drugs and pathways that induce cell death independently of p53 deserves substantial attention. Induction of cancer cell death is challenging when p53 and other apoptotic pathways are inactivated, and requires chemotherapeutics that induce cell death pathways that do not require the tumor suppressor p53, as at least 50 percent of cancers lack a functional p53 pathway. We published that different mitomycins, which are alkylating agents, activate p53-dependent and p53-independent cell death. We see the mitomycin derivative 10-decarbamyl mitomycin C (DMC), as opposed to mitomycin C (MC), can rapidly activate a p53-independent cell death pathway which lacks markers of apoptotic death. DMC-induced cell death is a good model for identifying targets for the induction of p53-independent cell death pathways, such as necrosis and autophagy. Our central hypothesis is that DMC provokes p53-independent cell death due to specific DNA adducts formed and that elucidating the pathway(s) will enable efficient drug design parameters. Identifying the mechanisms by which DMC induces cell death is the focus of this proposal and will be a first step toward developing drugs to strategically induce cell death for the many cancers lacking functional p53 pathways. Despite the importance of p53-independent cell death, little is known about the activation of such pathways. Four aims are proposed that will use a human cancer cell line with inducible p53 and its isogenic pair (without p53) to examine p53 dependency and independency in cell death signaling, and C. elegans to serve as a preclinical model system. (1) Identify the human signal transduction pathways required for cell death in the presence and absence of p53 that are activated and/or repressed by DMC and MC. (2) Analyze the ability of DMC and MC DNA adducts in vitro and in vivo to recruit DNA repair proteins in the presence and absence of p53. (3) Perform comparative analysis of the influence of the p53 pathway and the autophagy pathway on the chemotherapeutic DNA damage-induced cell death in C. elegans and human cell systems. (4) Obtain R01 funding for my laboratory research. There is a gap in knowledge as to how to target for p53-independent cell death. Knowledge of the signaling mechanisms for p53-independent cell death pathways will help in targeting drugs to patients who have cancers that lack functional p53.

描述（由申请人提供）：鉴定独立于 p53 诱导细胞死亡的药物和途径的需要值得大量关注。当 p53 和其他凋亡途径失活时，诱导癌细胞死亡具有挑战性，并且需要诱导不需要肿瘤抑制因子 p53 的细胞死亡途径的化疗药物，因为至少 50% 的癌症缺乏功能性 p53 途径。我们发表了不同的丝裂霉素（烷化剂）可激活 p53 依赖性和 p53 依赖性细胞死亡。我们发现丝裂霉素衍生物 10-去氨甲酰丝裂霉素 C (DMC) 与丝裂霉素 C (MC) 不同，可以快速激活不依赖于 p53 的细胞死亡途径，该途径缺乏细胞凋亡标记。 DMC 诱导的细胞死亡是识别诱导 p53 独立细胞死亡途径（例如坏死和自噬）的靶标的良好模型。我们的中心假设是，DMC 由于形成了特定的 DNA 加合物而引发不依赖于 p53 的细胞死亡，并且阐明该途径将有助于实现有效的药物设计参数。确定 DMC 诱导细胞死亡的机制是该提案的重点，这将是开发药物以策略性诱导许多缺乏功能性 p53 途径的癌症细胞死亡的药物的第一步。尽管不依赖于 p53 的细胞死亡很重要，但人们对此类途径的激活知之甚少。提出了四个目标，即使用具有诱导型 p53 及其同基因对（不含 p53）的人类癌细胞系来检查细胞死亡信号传导中的 p53 依赖性和独立性，并使用秀丽隐杆线虫作为临床前模型系统。 (1) 鉴定在存在和不存在 p53 的情况下细胞死亡所需的人类信号转导途径，这些途径被 DMC 和 MC 激活和/或抑制。 (2) 分析DMC和MC DNA加合物在p53存在和不存在的情况下体外和体内募集DNA修复蛋白的能力。 (3)对比分析p53途径和自噬途径对秀丽隐杆线虫和人体细胞系统化疗DNA损伤诱导的细胞死亡的影响。 (4) 为我的实验室研究获得R01资助。关于如何靶向 p53 独立的细胞死亡存在知识空白。了解 p53 独立细胞死亡途径的信号传导机制将有助于将药物靶向治疗缺乏功能性 p53 的癌症患者。