The 10th International MDM2 Workshop

项目总结/摘要 p53蛋白是人类癌症中最常见的突变基因，通过以下途径发挥肿瘤抑制因子的作用： 转录调节许多参与细胞周期进程和凋亡的下游靶基因。 MDM 2及其同源物MDM 4（也称为MDMX）是p53的两种最重要的负调节剂 通过作为E3泛素连接酶复合物促进p53降解和通过物理结合抑制p53降解， p53的转录功能。这些蛋白质在大约30%的人类癌症中也过表达。 MDM 2/MDM 4的过表达不仅抑制p53功能，而且表现出p53非依赖性致癌作用。 活动有趣的是，MDM 2和MDM 4的基因扩增与不良的过度进展相关。 在一个患者子集中对抗PDL 1癌症免疫疗法的反应。因此，MDM 2和MDM 4的抑制剂 已被开发用于抑制它们的致癌活性并重新激活肿瘤中的野生型p53。重要的是， 一些MDM 2/MDM 4抑制剂正在进行临床试验。2001年，第一届国际MDM 2研讨会在 英国，主要是为了应对与p53及其负相关的研究的显著增加。 调节剂MDM 2/MDM 4，以及对靶向MDM 2/MDM 4/p53的药物发现的强烈需求。的 * 扩大科学界对MDM 2/MDM 4的研究，并需要继续进行这一领域的研究， 多学科协作方法进一步使第二次千年发展目标讲习班成为必要。述mdm 2 讲习班每两年或三年在美国和欧洲轮流举办， 汇集p53/MDM 2领域，展示最新研究，促进合作和交流， 试剂事实上，p53和MDM 2研讨会已经成为长期科学研究的重要平台。 MDM 2-p53通路的交流和新的研究者。第10届国际MDM 2研讨会将于 在日本东京新建的国家癌症中心研究所（NCCRI）的礼堂， 2023年10月15日至18日。这将是第一次在日本举办的国际p53/MDM 2研讨会。的 会议将由Rieko Ohki博士（日本东京NCCRI）、Koji Itahana博士（杜克-NUS医疗 学校，新加坡）和岩沼友雄博士（美国密苏里州儿童慈善研究所）。值得注意的是，由于 COVID-19，自11月9日第九届MDM 2研讨会以来，我们已经超过4年没有举办MDM 2研讨会了 2018年4月7日在佛罗里达。我们期待更多的参与者以更高的热情参加第十届MDM 2研讨会， 与以前的MDM 2研讨会相比。大量的美国研究人员，包括 国际组织委员会（16人中有11人，妇女占38%），预计将参加并受益于 了那次会议因此，我们正在申请R13资金，以支持这一重要而令人兴奋的国际会议 这将激励美国的研究，促进p53/MDM 2领域的科学进步和相互作用。资金 要求支持旨在促进美国调查人员参与的三个重要具体目标 和实习生。

Project Summary/Abstract The p53 protein is the most frequently mutated gene in human cancers and functions as a tumor suppressor by transcriptionally regulating numerous downstream target genes involved in cell cycle progression and apoptosis. MDM2 and its homolog MDM4 (also known as MDMX) are two of the most important negative regulators of p53 by acting as an E3 ubiquitin ligase complex to promote p53 degradation and by physical binding to inhibit the p53’s transcriptional function. These proteins are also overexpressed in approximately 30% of human cancers. Overexpression of MDM2/MDM4 not only inhibits p53 function, but also shows p53-independent oncogenic activities. Intriguingly, gene amplification of MDM2 and MDM4 is associated with adverse hyperprogressive response to anti-PDL1 cancer immunotherapy in a subset of patients. Thus, inhibitors for MDM2 and MDM4 have been developed to inhibit their oncogenic activities and to reactivate wild-type p53 in tumors. Importantly, some MDM2/MDM4 inhibitors are in clinical trials. The first International MDM2 Workshop, held in 2001 in the United Kingdom, was primarily in response to a significant increase in the research related to p53 and its negative regulators MDM2/MDM4, as well as strong demand for drug discovery targeting MDM2/MDM4/p53. The expansion of the scientific community studying MDM2/MDM4 and the need to pursue this area of research with a collaborative multidisciplinary approach have further made the MDM2 Workshop necessary. The MDM2 Workshop is held every two or three years, at locations alternating between the United States and Europe, to bring together the p53/MDM2 field, present the latest research, and facilitate collaboration and exchange of reagents. Indeed, both the p53 and MDM2 Workshops have become important platforms for long-term scientific exchange and new investigators of the MDM2-p53 pathway. The 10th International MDM2 Workshop will be held at an auditorium of the newly built National Cancer Center Research Institute (NCCRI) in Tokyo, Japan, on October 15-18, 2023. This will be the first International p53/MDM2 Workshop organized and held in Japan. The meeting will be co-organized by Dr. Rieko Ohki (NCCRI, Tokyo, Japan), Dr. Koji Itahana (Duke-NUS Medical School, Singapore), and Dr. Tomoo Iwakuma (Children’s Mercy Research Institute, MO, USA). Notably, due to COVID-19, we have not had the MDM2 Workshop for over 4 years, since the 9th MDM2 Workshop on November 4-7, 2018 in Florida. We expect more participants with higher enthusiasm for this 10th MDM2 Workshop, as compared with the previous MDM2 Workshops. Significant numbers of US researchers, including the international organizing committee (11 out of 16, 38% women), are expected to participate in and benefit from the meeting. Hence, we are applying for R13 funding to support this important and exciting international meeting that will energize research in US and promote scientific progress and interactions in the p53/MDM2 field. Funds are requested to support three important specific aims designed to promote participation of the US investigators and trainees.