Functions and Activities of p53 and Mdm2 in Normal and Cancer Cells

p53 和 Mdm2 在正常细胞和癌细胞中的功能和活性

• 批准号: 10657532
• 负责人: Carol Prives
• 金额: $ 85.59万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-17 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657532
• 关键词: Animals; Award; Binding; Biological Markers; Cancer Patient; Cell Cycle Arrest; Cell Death; Cell Line; Cells; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; Cytostatics; DNA Repair; DNA Sequence; Diagnosis; Diagnostic; Genes; Genetic Transcription; Goals; Homologous Gene; Human; In Vitro; Inherited; Laboratories; Lead; Li-Fraumeni Syndrome; Malignant Neoplasms; Mediating; Metabolic; Mutation; Normal Cell; Oncogenic; Outcome; Peptides; Pharmaceutical Preparations; Play; Process; Proteins; Reagent; Recording of previous events; Research; Research Personnel; Resolution; Role; Series; Site; Stimulus; Stress; TP53 gene; Therapeutic; Therapeutic Agents; Tissues; Tumor Suppression; Tumor Suppressor Proteins; Untranslated RNA; Work; antitumor agent; cancer cell; cytotoxic; genotoxicity; in vivo; mutant; new technology; novel; novel diagnostics; novel strategies; novel therapeutics; prevent; programs; senescence; single molecule; small molecule; therapeutically effective; tool; tumor; tumorigenesis

Functions and Activities of p53 and Mdm2 in Normal and Cancer Cells. The p53 protein, a major suppressor of cancer in animals and humans, is a DNA sequence specific regulator of transcription of hundreds of genes whose products mediate cellular outcomes such as cell cycle arrest, cell death, senescence, metabolic changes, DNA repair and others that are consistent with tumor suppression. While a potent regulator of such processes in cells undergoing various forms of genotoxic or oncogenic stress, if allowed to function unchecked, p53 can be damaging or even lethal to cells and tissues. Keeping p53 under tight control is therefore as important as allowing it to function when needed. The two proteins that play the most central role in suppressing p53 are Mdm2 and its homologue MdmX. Over half of all human malignancies (depending on the tumor type) harbor wild-type p53, which if released from Mdm2/X, might be effective as a cytostatic or cytotoxic anti-tumor agent. Yet reagents (peptides and small molecules) that prevent Mdm2 from binding to p53 have not yet been fully realized as effective therapeutic agents. Similarly, there few effective drugs in the clinic that prevent the oncogenic activities of mutant p53. Further, increasing lines of evidence document p53-independent roles of Mdm2 and MdmX in cancer cells that can be exploited for therapeutic and diagnostic purposes. The work proposed in this application for an Outstanding Investigator Award follows a long history of contributions in the laboratory of the PI to our understanding p53, Mdm2 and MdmX that continue to the present day. The plans going forward build on new findings in the PI's lab, and incorporate novel technologies in order to gain more global and mechanistic information about the p53/Mdm axis. The research proposed will extend recent discoveries related to (i) a novel mechanism by which Mdm2 degrades p53 and the possibility that this finding can lead to new therapeutics that prevent Mdm2 degradation of wild-type p53 or conversely facilitate Mdm2 degradation of oncogenic mutant forms of p53, (ii) a series of CRISPR-derived cell lines harboring unique Li-Fraumeni-Syndrome p53 mutations; (iii) p53- independent roles of Mdm2 and MdmX that may either prevent or support oncogenesis, (iv) long non-coding RNAs that are p53 targets and which may provide new biomarkers in human cancers; (v) new approaches to understand how p53 identifies its sites in vitro and in vivo and, (vi) examination at single molecule resolution the localization of wild-type and mutant forms of p53 and Mdm2 after different stimuli. The long term goals of this program will hopefully lead to new tools for diagnosis and treatment of sporadic and inherited cancers.

正常和癌细胞中p53和MDM2的功能和活性。 p53蛋白是动物和人类癌症的主要抑制剂，是DNA序列 数百个基因转录的特定调节剂，其产物介导细胞的基因 结局，例如细胞周期停滞，细胞死亡，衰老，代谢变化，DNA修复和 其他与肿瘤抑制一致的。而在 如果允许运行各种形式的遗传毒性或致癌应激的细胞 未检查的p53可能会破坏细胞和组织。保持P53紧紧 因此，控制与允许其在需要时运行一样重要。两种蛋白质 在抑制p53中发挥最重要的作用是MDM2及其同源MDMX。超过一半 所有人类恶性肿瘤（取决于肿瘤类型）都有野生型P53，如果释放 从MDM2/X起，可能是细胞抑制剂或细胞毒性抗肿瘤剂的有效性。但是试剂 （肽和小分子）预防MDM2与p53结合的（尚未完全 被认为是有效的治疗剂。同样，诊所中很少有有效的药物 防止突变体p53的致癌活性。此外，增加证据文件线 MDM2和MDMX在癌细胞中无关的作用，可以利用用于治疗的 和诊断目的。本申请中提出的作品针对杰出的调查员 奖项遵循PI实验室的悠久贡献历史 p53，MDM2和MDMX一直持续到今天。未来的计划建立在新的基础上 PI实验室中的发现，并合并新技术以获得更多的全球性和 有关p53/MDM轴的机械信息。提出的研究将扩大最近的 与（i）MDM2降低p53和可能性的新型机制有关的发现 这一发现可以导致新的治疗剂，以防止MDM2野生型p53或 相反，p53的致癌突变体形式的MDM2降解，（ii）一系列 CRISPR衍生的细胞系具有独特的Li-Fraumeni-Syndrome P53突变； （iii）p53- MDM2和MDMX的独立作用，可以预防或支持肿瘤发生，（iv） 长的非编码RNA是p53靶标，可以为人类提供新的生物标志物 癌症； （v）了解p53如何在体外和体内识别其位置的新方法以及 （vi）在单分子分辨率下检查野生型和突变形式的定位 p53和MDM2不同刺激后。该计划的长期目标有望导致 用于零星和遗传癌的诊断和治疗的新工具。

项目成果

p53 Frameshift Mutations Couple Loss-of-Function with Unique Neomorphic Activities.

• DOI: 10.1158/1541-7786.mcr-20-0691
• 发表时间: 2021-09
• 期刊: Molecular cancer research : MCR
• 作者: Tong DR;Zhou W;Katz C;Regunath K;Venkatesh D;Ihuegbu C;Manfredi JJ;Laptenko O;Prives C
• 通讯作者: Prives C

The roles and regulation of MDM2 and MDMX: it is not just about p53.

• DOI: 10.1101/gad.347872.120
• 发表时间: 2021-05-01
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Klein AM;de Queiroz RM;Venkatesh D;Prives C
• 通讯作者: Prives C