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

• 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
• 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

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）：需要识别独立于p53的药物和途径的途径值得大大关注。当p53和其他凋亡途径被灭活时，癌细胞死亡的诱导是有挑战性的，并且需要诱导不需要肿瘤抑制p53的细胞死亡途径的化学治疗疗法，因为至少50％的癌症缺乏功能性p53途径。我们发表了烷基化剂的不同丝裂霉素激活p53依赖性和p53独立的细胞死亡。我们看到丝裂菌素衍生物10-核酸丝霉素C（DMC）与丝裂霉素C（MC）相反，可以迅速激活缺乏垂体死亡标记的p53独立的细胞死亡途径。 DMC诱导的细胞死亡是识别诱导p53独立的细胞死亡途径（例如坏死和自噬）的靶标。我们的中心假设是，由于形成了特定的DNA加合物，DMC挑衅p53独立的细胞死亡，并且阐明途径将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，它将成为开发药物以策略性地诱导许多缺乏功能性p53途径的癌症的细胞死亡的第一步。尽管p53独立的细胞死亡很重要，但对这种途径的激活知之甚少。提出了四个目的，它将使用诱导p53及其等源性对（无p53）的人类癌细胞系检查细胞死亡信号的p53依赖性和独立性，而秀丽隐杆线虫则用作临床前模型系统。 （1）在存在和/或被DMC和MC抑制的p53的存在和不存在的情况下，确定细胞死亡所需的人类信号转导途径。 （2）在存在和不存在p53的情况下，在体外和体内分析DMC和MC DNA加合物在体外和体内募集DNA修复蛋白的能力。 （3）对p53途径和自噬途径对化学治疗性DNA损伤诱导的秀丽隐杆线虫和人类细胞系统中细胞死亡的影响进行比较分析。 （4）为我的实验室研究获得R01资金。 关于如何靶向p53独立的细胞死亡，知识存在差距。了解p53独立的细胞死亡途径的信号传导机制将有助于将药物靶向缺乏功能性p53的癌症患者。

项目成果

Decarbamoyl mitomycin C (DMC) activates p53-independent ataxia telangiectasia and rad3 related protein (ATR) chromatin eviction.

• DOI: 10.1080/15384101.2014.997517
• 发表时间: 2015
• 期刊: Cell cycle (Georgetown, Tex.)
• 作者: Xiao G;Kue P;Bhosle R;Bargonetti J
• 通讯作者: Bargonetti J