Roles and Regulation of wild-type and mutant forms of p53

总体汇总 在过去的15年里，我们的项目CA 87497一直是高效和互动的。 该计划的未来目标是研究环境依赖的肿瘤抑制作用， 野生型p53，并阐明癌症相关的突变形式的p53如何促进肿瘤发生。 我们将研究新发现的途径，其中野生型和突变型p53蛋白 操作和各自的作用，在调节表观基因组和表征新 p53的转录靶点。除了现任成员外，卡罗尔·普里夫斯博士，阿诺德 莱文、斯科特·洛和卡洛斯·科登-卡多，我们请来了布伦特·斯托克韦尔博士， 约翰佩特里尼谁每个贡献新的和令人兴奋的方向，接口与现有的 项目我们的方法包括细胞生物学，化学生物学，生物化学，蛋白质组学， 显微镜、生物信息学、功能基因组学、小鼠建模以及人类和小鼠 病理我们的研究是高度转化和相关的人类疾病，重点是 乳腺癌、肝癌和淋巴瘤。项目1（Prives）将研究突变型p53的获得， 利用基于细胞的测定、基因表达谱分析和蛋白质组学研究功能活性。 项目1将阐明突变型p53如何以及为什么刺激甲羟戊酸途径，而野生型p53则刺激甲羟戊酸途径。 p53型抑制这一相同的途径，并将获得机制信息， 突变型p53促进核小体重塑。项目2（Stockwell）将确定机制 这是他的团队发现的。计划工作将确定 p53靶点p21如何在负反馈回路中起作用以抑制铁凋亡，p53如何 通过对甲羟戊酸途径的影响调节铁凋亡，以及营养缺乏如何 调节p53及其对铁凋亡的影响。项目3（Petrini）将量化和确定 乳腺癌癌基因激活引起的p53依赖性表观遗传学改变的定位 上皮细胞，并将决定这种新的途径是否在造血细胞中起作用， 并评估其对抑制淋巴瘤和髓性白血病的重要性。项目 4（Lowe）使用先进的遗传和基因组工具， p53介导的不同组织肿瘤抑制机制的小鼠模型 和遗传背景，以及新的p53突变体在肿瘤发生和发展中的作用， vivo.它还将探讨铁凋亡在肿瘤抑制中的作用，以及铁凋亡的失调是如何影响肿瘤的生长的。 p53介导的基因抑制程序包括甲羟戊酸途径有助于肿瘤 上维护计划中的研究将广泛依赖于三个核心：核心A（私人）， 将在行政上支持项目内的所有互动，生物信息学核心B 这将为每个项目提供关键的计算支持，以帮助 发现在不同情况下由突变型和野生型p53调控的基因和途径。 核心B将测试新的假设并鉴定野生型和突变型p53的新调节剂。的 分子系统病理学核心C（Cordon-Cardo）将提供以下关键信息 包括衍生自甲羟戊酸和铁蛋白的新的分子生物标志物的人类肿瘤 途径。核心C也将量化异染色质标记，并将研究突变体的生物标志物。 肝脏和淋巴瘤样本中的p53、干细胞和新的抑制靶点。

Overall Summary For the past 15 years our Program Project CA87497 has been highly productive and interactive. The future goals of this program are to study the context-dependent tumor suppressive roles of wild-type p53, and to elucidate how cancer related mutant forms of p53 promote oncogenesis. We will investigate newly discovered pathways in which wild-type and mutant p53 proteins operate and their respective roles in regulating the epigenome and characterize new transcriptional targets of p53. In addition to the current members, Drs Carol Prives, Arnold Levine, Scott Lowe and Carlos Cordon-Cardo, we have brought in Drs Brent Stockwell and John Petrini who each contribute new and exciting directions that interface with the existing projects. Our approaches include cell biology, chemical biology, biochemistry, proteomics, microscopy, bioinformatics, functional genomics, mouse modeling and human and mouse pathology. Our research is highly translational and relevant to human disease, focusing on breast cancer, liver cancer and lymphoma. Project 1 (Prives) will investigate mutant p53 gain of function activities employing cell-based assays, gene expression profiling and proteomics. Project 1 will elucidate how and why mutant p53 stimulates the mevalonate pathway, while wild- type p53 represses this same pathway, and will obtain mechanistic information as to how mutant p53 facilitates nucleosome remodeling. Project 2 (Stockwell), will define mechanisms that govern p53 regulation of ferroptosis, which his group discovered. Planned work will define how the p53 target p21 acts in a negative feedback loop to restrain ferroptosis, how p53 regulates ferroptosis through its effects on the mevalonate pathway, and how nutrient deficiency regulates p53 and its impact on ferroptosis. Project 3 (Petrini) will quantify and determine the location of p53-dependent epigenetic changes induced by oncogene activation in mammary epithelium and will determine whether this novel pathway is operative in hematopoietic cells, and assess its importance for suppression of lymphomagenesis and myeloid leukemia. Project 4 (Lowe) uses advanced genetic and genomic tools together with novel genetically-engineered mouse models to explore mechanisms of p53-mediated tumor suppression in different tissue and genetic contexts, and the role of novel p53 mutants on tumor initiation and progression in vivo. It will also explore the role of ferroptosis in tumor suppression and how deregulation of p53-mediated gene repression programs including the mevalonate pathway contributes to tumor maintenance. The planned research will rely extensively on three cores: Core A (Prives), that will administratively support all interactions within the program, the Bioinformatics Core B (Levine) that will provide crucial computational support for each project in order to aid in the discovery of genes and pathways regulated by mutant and wild-type p53 in different contexts. Core B will test new hypotheses and identify new modulators of wild-type and mutant p53. The Molecular Systems Pathology Core C (Cordon-Cardo) will provide critical information regarding human tumors including new molecular biomarkers derived from mevalonate and ferroptotic pathways. Core C will also quantify heterochromatic marks and will study biomarkers of mutant p53, stem cells, and new repression targets in liver and lymphoma samples.