Mechanisms of Protein 4.1B Tumor Suppression

蛋白质4.1B肿瘤抑制机制

• 批准号: 6613878
• 负责人: VICTORIA A HILDEBRANDT
• 金额: $ 4.64万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-17 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6613878
• 关键词: CD44 molecule; SDS polyacrylamide gel electrophoresis; artificial immunosuppression; cell cell interaction; central nervous system neoplasms; flow cytometry; immunocytochemistry; membrane proteins; meningioma; neoplasm /cancer genetics; neoplastic process; postdoctoral investigator; protein binding; protein structure function; site directed mutagenesis; terminal nick end labeling; tumor suppressor genes; tumor suppressor proteins; western blottings

DESCRIPTION (provided by applicant): The development of cancer involves the inactivation of specific genes involved in growth regulation. Recent work from our laboratory and others have identified two tumor suppressor genes that belong to the Protein 4.1 family of molecules (the NF2 gene product, merlin, and Protein 4.1B) and are deleted in brain, breast, and lung cancers. In specific brain tumors (meningiomas), Protein 4.1B expression is lost early in tumor development and may represent an initiating event in brain tumorigenesis. We have previously shown that (a) Protein 4.1B suppresses meningioma cell growth in vitro, (b) Protein 4.1B associates with both CD44 and 14-3-3, and (c) the minimal growth suppressor domain of Protein 4.1 B maps to a region that mediates binding to both CD44 and 14-3-3. In this proposal, I plan to test the hypothesis that the ability of Protein 4.1B to suppress meningioma cell growth requires regulated interactions with both CD44 and 14-3-3. Specifically, I wish to (1) identify and characterize the minimal domain of Protein 4.1B required for growth suppression, (2) define the molecular determinants within the Protein 4.1B growth suppressor domain that mediate interactions with CD44 and 14-3-3, and (3) determine whether the binding of Protein 4.1B to CD44 and 14-3-3 is critical for Protein 4.1B growth suppression. These studies are focused on elucidating the mechanism(s) underlying tumor suppression of one of the critical growth regulators important in brain tumor formation.

描述（由申请人提供）：癌症的发展涉及对参与生长调节的特定基因的失活。我们实验室和其他人的最新工作已经确定了属于蛋白质4.1分子家族（NF2基因产物，Merlin和蛋白4.1B）的两个肿瘤抑制基因，并在脑，乳腺癌和肺癌中删除。在特定的脑肿瘤（脑膜瘤）中，蛋白质4.1b表达在肿瘤发育早期丧失，可能代表脑肿瘤发生的起始事件。我们先前已经表明，（a）蛋白4.1b在体外抑制了脑膜瘤细胞的生长，（b）蛋白4.1b与CD44和14-3-3均可抑制蛋白4.1b辅助，以及（c）蛋白4.1 B地图的最小生长抑制域4.1 b地图与介导与CD44和14-3-3结合的区域。 在此提案中，我计划检验以下假设：蛋白质4.1b抑制脑膜瘤细胞生长的能力需要调节CD44和14-3-3的相互作用。 具体而言，我希望（1）识别并表征抑制生长所需的蛋白质4.1b的最小结构域，（2）定义蛋白质4.1b生长抑制域内的分子决定因，这些分子决定因素介导了与CD44和14-3-3相互作用的相互作用，并且（3）（3）确定蛋白质4.1b对CD44和14-3-3-3-3-3-3-3-3-蛋白质的结合是否至关重要。这些研究的重点是阐明对脑肿瘤形成重要的关键生长调节剂之一的肿瘤抑制的机制。