Role of DN-p63 in Preservation of Self Renewal

DN-p63 在保护自我更新中的作用

• 批准号: 6917604
• 负责人: James DiRenzo
• 金额: $ 24.05万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6917604
• 关键词: Adenoviridae; DNA binding protein; MCF7 cell; apoptosis; breast neoplasms; carcinogenesis; cell cycle; cell differentiation; cell growth regulation; cell proliferation; chromatin immunoprecipitation; gene expression; gene mutation; genetic promoter element; genetically modified animals; laboratory mouse; mammary epithelium; molecular oncology; neoplasm /cancer genetics; p53 gene /protein; protein isoforms; small interfering RNA; transcription factor; transfection /expression vector

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to test the hypothesis that factors, which promote the expression or activity of DN-p63 contribute to the preservation of self-renewal in basal epithelia, and factors that oppose the expression or activity of DN-p63 contribute to the forfeiture of self-renewing capacity. There is abundant evidence that DN-p63 is required for the preservation of self-renewal, however the precise mechanisms by which it achieves this have not been fully elucidated. We define self-renewal as the ability to retain proliferative capacity, resist differentiation signals and avoid developmentally regulated apoptosis. Several recent studies have indicated that cancer initiation is a condition of unregulated self-renewal. This underscores the importance of identifying the mechanisms that preserve and regulate self-renewal and defining the consequences of their subversion. Specific Aim 1 intends to evaluate the contributions of DNp63 to retention of proliferative capacity and resistance to cellular differentiation signals. Specific Aim 2 intends to evaluate the contributions of DN-p63 to resistance to apoptosis, and the role of DN-p63 in mediating an appropriate response to genotoxic stress. Specific Aim 3 intends to address the developmental consequences of forfeiture of self-renewal that is mediated by disruption of DN-p63. The goal of Specific Aim 3 is to identify and validate gene-regulatory events that result from disruption of DN-p63 and to determine if these events mediate the forfeiture of self-renewal. Our previous studies indicate that DNp63 is a direct target of p53, however genetic analysis of p53 has not indicated a self-renewal deficiency. Specific Aim 4 intends to identify and characterize a p53-independent mechanism that promotes expression of DN-p63, and to determine if this mechanism is responsible for p53-independent expression of DN-p63. Successful completion of these aims will offer insights into the molecular mechanisms underlying the decision of self-renewing basal progenitors to either preserve or forfeit self-renewing capacity.

描述（由申请人提供）：该提案的长期目标是检验以下假设：促进DN-P63的表达或活性的因素有助于保存基础上皮中的自我更新，以及反对DN-P63的表达或活性的因素有助于没收自我恢复能力。 有大量的证据表明，保存自我更新需要DN-P63，但是实现这一目标的确切机制尚未完全阐明。 我们将自我更新定义为保持增殖能力，抵抗分化信号并避免发育调节的细胞凋亡的能力。 最近的一些研究表明，癌症的开始是不受监管的自我更新的条件。 这强调了确定保留和调节自我更新并定义其颠覆后果的机制的重要性。 具体目标1旨在评估DNP63对保留增殖能力和对细胞分化信号的抗性的贡献。 具体目标2旨在评估DN-P63对凋亡耐药性的贡献，以及DN-P63在介导对遗传毒性应激的适当反应中的作用。 特定目标3旨在解决没收由DN-P63中断介导的自我更新的发展后果。 特定目标3的目的是识别和验证由DN-P63中断导致的基因调节事件，并确定这些事件是否介导了没收自我更新。 我们以前的研究表明，DNP63是p53的直接靶标，但是p53的遗传分析并未表明自我更新缺陷。 特定的目标4旨在识别和表征p53独立的机制，该机制促进了DN-P63的表达，并确定该机制是否负责DN-P63的p53无依赖性表达。 这些目标的成功完成将提供有关自我更新基础祖先以保持或没收自我更新能力的决定的分子机制的见解。