MDM2 AS A NEGATIVE REGULATOR OF P21 WAF1/CIP1

MDM2 作为 P21 WAF1/CIP1 的负调节因子

• 批准号: 7167158
• 负责人: RUIWEN ZHANG
• 金额: $ 25.45万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7167158
• 关键词: Antisense Oligonucleotides; Applications Grants; Binding; CDKN1A gene; Doctor of Philosophy; Genes; Genetic; Genotype; Growth; Half-Life; Human; In Vitro; Knowledge; MDM2 gene; MDM2 gene; Malignant Neoplasms; Mediating; Oncogene Proteins; Oncogenes; Pathway interactions; Personal Satisfaction; Prevention; Prevention therapy; Property; Protein Overexpression; Regulation; Role; Small Interfering RNA; TP53 gene; Translating; Ubiquitination; Xenograft Model; Xenograft procedure; cancer cell; cancer chemoprevention; cancer prevention; carcinogenesis; chemotherapy; in vivo; inhibitor/antagonist; multicatalytic endopeptidase complex; novel; oncoprotein p21; outcome forecast; tumor growth; tumor progression; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): The long-term objectives of this project are to determine the role of MDM2 oncogene in p21 regulation, to evaluate the potential of MDM2 and p21as novel targets for cancer chemoprevention and chemotherapy, and to translate these findings into more rational prevention and treatment of human cancers. The expression of p21 is under the control of p53. However, p21 is also regulated by p53-independent pathways. The MDM2 oncogene is overexpressed in many human cancers, with the MDM2 levels being associated with tumor progression and poor prognosis. MDM2 has a role in the regulation of p53 stability and activity. In addition, MDM2 also has p53-independent activity, which may be associated with its carcinogenic properties. Preliminary studies have indicated that MDM2 has an important role in regulation of p21. The inhibition of MDM2 with anti-MDM2 antisense oligonucleotide or siRNA targeting MDM2 significantly elevates p21 protein levels in cancer cells (p53 null). In contrast, overexpression of MDM2 diminishes the p21 level, shortening the p21 half-life. MDM2 facilitates p21 degradation independent of ubiquitination and the E3 ligase function of MDM2. Instead, MDM2 promotes p21 degradation by facilitating binding of p21 with the proteasomal C8-subunit. MDM2 functions as a negative regulator of p21, an effect independent of both p53 and ubiquitination. This application seeks to further clarify the role and mechanisms of MDM2 oncogene as a negative regulator of p21, including three Specific Aims: 1). To determine the mechanisms by which MDM2 regulates p21 at transcriptional level; 2) To determine the mechanisms by which MDM2 regulates p21 at post-translational level; and 3) To determine the in vitro and in vivo activity of MDM2 and p21 human cancer growth and progression. These studies will generate knowledge on the mechanisms responsible for the p53-independent carcinogenic activities of MDM2 and evaluate the potential of these pathways for human cancer prevention and treatment.

描述（申请人提供）：该项目的长期目标是确定MDM2癌基因在p21调节中的作用，评估MDM2和p21作为癌症化学预防和化疗新靶点的潜力，并将这些发现转化为更合理的人类癌症预防和治疗。 p21的表达受p53的控制。然而，p21 也受到 p53 独立途径的调节。 MDM2 癌基因在许多人类癌症中过度表达，MDM2 水平与肿瘤进展和不良预后相关。 MDM2 具有调节 p53 稳定性和活性的作用。此外，MDM2还具有p53独立活性，这可能与其致癌特性有关。初步研究表明MDM2在p21的调节中具有重要作用。使用抗 MDM2 反义寡核苷酸或靶向 MDM2 的 siRNA 抑制 MDM2 可显着提高癌细胞中的 p21 蛋白水平（p53 无效）。相反，MDM2 的过度表达会降低 p21 水平，缩短 p21 半衰期。 MDM2 促进 p21 降解，与 MDM2 的泛素化和 E3 连接酶功能无关。相反，MDM2 通过促进 p21 与蛋白酶体 C8 亚基的结合来促进 p21 降解。 MDM2 充当 p21 的负调节因子，其作用独立于 p53 和泛素化。本申请旨在进一步阐明MDM2癌基因作为p21负调节因子的作用和机制，包括三个具体目标：1)。确定MDM2在转录水平调节p21的机制； 2) 确定MDM2在翻译后水平调控p21的机制； 3) 确定 MDM2 和 p21 人类癌症生长和进展的体外和体内活性。这些研究将产生有关 MDM2 的 p53 独立致癌活性机制的知识，并评估这些途径在人类癌症预防和治疗中的潜力。