The Role of MDM Proteins in Cell Growth and Tumorigenesis

MDM 蛋白在细胞生长和肿瘤发生中的作用

• 批准号: 8255364
• 负责人: STEPHEN JONES
• 金额: $ 31.56万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8255364
• 关键词: Adult; Affect; Amino Acid Substitution; Aneuploidy; Apoptosis; Biochemical; Biological Assay; Breast; Cell Death; Cell Proliferation; Cell physiology; Cells; Chromosomal Stability; Conflict (Psychology); DNA Damage; Data; Development; Epithelial; Epithelium; Gene Expression; Gene Targeting; Generations; Genes; Genetically Engineered Mouse; Growth; Homeostasis; Homologous Gene; Human; In Vitro; Knockout Mice; Learning; MDM2 gene; Maintenance; Malignant Neoplasms; Mammary Tumorigenesis; Maps; Mediating; Modeling; Modification; Mus; Mutation; Normal Cell; Null Lymphocytes; Oncogenes; Oncogenic; Patients; Phosphorylation; Play; Polyploidy; Property; Protein p53; Proteins; Regulation; Relative (related person); Reporting; Research; Role; Serine; Signal Transduction; Tissues; Transactivation; Transfection; Transgenic Mice; Transgenic Model; Tumor Suppression; Ubiquitination; Work; base; cancer therapy; cell growth; cell transformation; chromosome loss; clinically relevant; in vivo; malignant breast neoplasm; mdm2 protein; mouse model; mutant; neoplastic cell; overexpression; p53 Signaling Pathway; protein complex; public health relevance; research study; response; small molecule; theories; therapeutic target; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Mdm2 and MdmX (also known as Mdm4) are key regulators of the p53 tumor suppressor. Previous work by our lab and by many other groups has determined that these MDM proteins complex with p53 and inhibit p53 functions, with Mdm2 inducing p53 ubiquitination and proteosomal degradation, and MdmX inhibiting p53 transactivation of p53 target gene expression. As such, Mdm2 and MdmX act as critical negative regulators of p53 tumor suppressing functions, and amplification of either the MDM2 or MDMX gene is observed in a significant percentage of human tumors. In this proposal, we summarize the progress we have made in our previous studies on p53 regulation by MDM and other cellular proteins. We also describe our very recent studies examining in vitro the effects of Mdm2 phosphorylation in the regulation of p53 stability, as well as our discovery of p53-independent roles for MdmX in suppressing proliferation and tumorigenesis in p53-null cells and mice. Based upon our preliminary data, we have generated new Mdm2 mouse models bearing amino acid substitutions in Mdm2 in order to examine in vivo the effects of Mdm2 phosphorylation on Mdm2-MdmX-p53 signaling and on p53 functions in development and tumor suppression. We also propose to further characterize p53-independent functions of MdmX in the regulation of cell transformation and chromosomal stability. Proposed research includes the generation of MdmX transgenic mice to model MdmX overexpression observed in human breast cancer, and to permit further exploration of the oncogenic and tumor suppressing capacity of MdmX in mammary tumorigenesis. This research should greatly increase our understanding of the roles of these MDM proteins in regulating cell growth and death, and the functional relationship between these homologues in DNA damage signaling and in p53-dependent and p53-independent suppression of cancer. PUBLIC HEALTH RELEVANCE: Mdm2 and MdmX (also known as Mdm4) are key negative regulators of the p53 tumor suppressor. Although much has been learned from transfection studies and from biochemical assays about the interconnecting roles of Mdm2 and MdmX in regulating p53, analysis of genetically modified mice has proven critical in substantiating the numerous and often conflicting models proposed for Mdm2 and MdmX regulation of p53 functions, and in developing new theories regarding the function of MDM proteins in cancer. We propose to analyze new mouse models to explore the effects of Mdm2 phosphorylation on Mdm2 and MdmX levels and on p53 functions in vivo. We also propose to continue our MdmX studies in cells and in mice to better understand and define the p53-independent roles for MdmX in transformation and chromosomal stability. We will also generate new MdmX transgenic models to explore p53- dependent and p53-independent effects of MdmX in mammary tumorigenesis. The results of these experiments will have clinical relevance, as an understanding of the regulatory mechanisms that control p53 activity in normal cell growth and in tumorigenesis is a critical prerequisite to developing new therapies to treat cancer in the significant percentage of patients who present with tumors bearing alterations in the Mdm2-MdmX-p53 signaling pathway.

描述（由申请人提供）：MDM2和MDMX（也称为MDM4）是p53肿瘤抑制剂的关键调节剂。我们实验室和许多其他组的先前工作已经确定，这些MDM蛋白与p53复合并抑制p53功能，MDM2诱导p53泛素化和蛋白质体降解，MDMX抑制p53靶标基因表达的p53反式化。因此，MDM2和MDMX充当p53肿瘤抑制功能的关键负调节剂，并且在很大一部分人类肿瘤中观察到了MDM2或MDMX基因的扩增。在此提案中，我们总结了MDM和其他细胞蛋白对P53调控的先前研究中所取得的进展。我们还描述了我们最近在体外研究的研究，该研究在体外研究了MDM2磷酸化对P53稳定性调节的影响，以及我们发现MDMX在抑制P53-Null细胞和小鼠中抑制P53独立的作用。基于我们的初步数据，我们已经在MDM2中生成了带有氨基酸取代的新的MDM2小鼠模型，以便在体内检查MDM2磷酸化对MDM2-MDMX-MDMX-P53信号传导以及对p53在发育和抑制肿瘤中的功能的影响。我们还建议进一步表征MDMX在细胞转化和染色体稳定性调节中的p53无关功能。拟议的研究包括生成MDMX转基因小鼠以建模在人类乳腺癌中观察到的MDMX过表达，并允许进一步探索MDMX在乳腺肿瘤发生中MDMX的抑制能力。这项研究应大大提高我们对这些MDM蛋白在调节细胞生长和死亡中的作用的理解，以及这些同源物在DNA损伤信号传导以及p53依赖性和p53独立抑制癌症中的功能关系。 公共卫生相关性：MDM2和MDMX（也称为MDM4）是p53肿瘤抑制剂的关键负调节剂。尽管从转染研究和生化测定法中学到了很多关于MDM2和MDMX在调节p53中的互连作用的研究，但对转基因小鼠的分析已证明是对MDM2和MDMX调节p53在p53和MDMX调节中构成的众多模型的重要性，并且在开发了新的MDMX调节中，以及在癌症方面的癌症，以及在MDMX方面的功能。我们建议分析新的小鼠模型，以探索MDM2磷酸化对MDM2和MDMX水平以及p53在体内功能的影响。我们还建议在细胞和小鼠中继续我们的MDMX研究，以更好地理解和定义MDMX在转化和染色体稳定性中的独立作用。我们还将生成新的MDMX转基因模型，以探索MDMX在乳腺肿瘤发生中的p53-依赖性和p53独立的作用。这些实验的结果将具有临床相关性，以了解控制正常细胞生长中p53活性和肿瘤发生的调节机制，是开发新的治疗癌症治疗癌症的关键先决条件，在大量患者中，患有MDM2-MDMX-MDMX-MDMX-MDMX-MDMX-P53信号途径的肿瘤发生变化的患者。