DISSECTING ROLES OF MTBP IN OSTEOSARCOMA METASTASIS

剖析 MTBP 在骨肉瘤转移中的作用

• 批准号: 7720778
• 负责人: Tomoo Iwakuma
• 金额: $ 34.63万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720778
• 关键词: Affect; Alleles; Attenuated; BAX gene; Bax protein; Binding; Binding Proteins; CDKN1A gene; Cell Cycle; Computer Retrieval of Information on Scientific Projects Database; Development; Funding; G1 Arrest; Genetic Transcription; Goals; Grant; Institution; Knock-out; Knockout Mice; Malignant Neoplasms; Metastatic Osteosarcoma; Mus; Mutate; Neoplasm Metastasis; Numbers; Osteoblasts; Pathway interactions; Patients; Play; Proteins; Protocols documentation; Research; Research Personnel; Resources; Role; Source; Stress; TP53 gene; Therapeutic; Tumor Suppressor Proteins; United States National Institutes of Health; Work; base; design; in vivo; inhibitor/antagonist; mutant; novel; oncoprotein p21; osteosarcoma; outcome forecast; tumor; yeast two hybrid system

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our long-term goal is to elucidate the impact of the Mdm2-p53 pathway in vivo on tumor development as a necessary prerequisite to the development of therapeutic protocols for attenuating cancer. p53 functions as a tumor suppressor and exerts this function by activating numerous downstream targets such as p21, BAX, PUMA, GADD45 as a transcription factor1. Mdm2 is a major inhibitor of p53 through physical binding and induction of p53 degradation2. The p53 gene is mutated in more than 50% of tumors, and Mdm2 is highly expressed in a variety of tumors, stressing the importance of the Mdm2-p53 pathway in tumor development 3-6. It should be noted that a significant number of tumors have wild-type p53 with Mdm2 over-expression. Interestingly, some patients with tumors in which p53 gene is mutated and Mdm2 is over-expressed are known to have a poorer prognosis, compared to patients with mutant p53 alone in tumors7, 8. These results suggest that Mdm2 also has p53-independent roles in tumor development. Recently, Mdm2 is found to inhibitory interact with other tumor suppressors such as Rb, PML, and p73, which may contribute to p53-independent roles of Mdm2 in tumor development9-15. One can assume that any proteins that affect Mdm2 function may have an impact on tumor development. Mdm2 Binding Protein (MTBP) was isolated by Boyd MT et al.16 using the yeast two hybrid system with Mdm2 as bait. Over-expression of MTBP causes G1 arrest of cell cycle, but the effect is nullified by simultaneous over-expression of Mdm2. Our working hypothesis is that MTBP plays a critical role in tumor development and metastasis. This hypothesis is based on our preliminary results using a conventional mtbp knockout mouse in which we observed that (1) 30% of mtbp heterozygous mice spontaneously developed tumors within 22 months, and (2) doubly heterozygous knockout mice for mtbp and p53 developed metastatic osteosarcomas. Based on these observations, the focus of this proposal is on the roles of MTBP in osteosarcoma metastasis and the functional characterization of this protein. The specific aims are designed to provide a comprehensive assessment of novel functions of MTBP, especially in osteosarcoma metastasis. Aim 1. To characterize osteosarcomas induced by loss of mtbp. Aim 2. To generate and characterize mice with conditional mtbp and/or p53 knockout alleles, specifically in osteoblasts. Aim 3. To isolate MTBP interacting proteins.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 我们的长期目标是阐明体内MDM2-P53途径对肿瘤发育的影响，这是开发用于减弱癌症治疗方案的必要前提。 p53用作肿瘤抑制剂，并通过激活诸如p21，bax，puma，gadd45等众多下游靶标作为转录因子1。 MDM2是通过p53降解的物理结合和诱导2的主要抑制剂2。 p53基因在超过50％的肿瘤中突变，MDM2在多种肿瘤中高度表达，这强调了MDM2-p53途径在肿瘤发育中的重要性3-6。应该注意的是，大量的肿瘤具有MDM2过表达的野生型P53。有趣的是，与仅在肿瘤中单独突变p53的患者相比，一些p53基因突变且MDM2过表达的肿瘤患者的预后较差。最近，发现MDM2抑制性与其他肿瘤抑制剂（如RB，PML和P73）相互作用，这可能有助于MDM2在肿瘤发育中的P53独立作用9-15。可以假设任何影响MDM2功能的蛋白质都可能对肿瘤发育产生影响。 MDM2结合蛋白（MTBP）通过Boyd Mt等人的16使用酵母两种杂种系统，其MDM2作为诱饵。 MTBP的过度表达导致G1停滞的细胞周期，但通过同时过表达MDM2，其效果无效。我们的工作假设是MTBP在肿瘤发育和转移中起着至关重要的作用。该假设基于我们的初步结果，使用常规的MTBP基因敲除小鼠，我们观察到（1）MTBP杂合小鼠中有30％在22个月内自发性化肿瘤，（2）双重杂合杂合敲除小鼠MTBP和p53开发的转移性转移性转移性替代型。基于这些观察结果，该建议的重点是MTBP在骨肉瘤转移中的作用以及该蛋白的功能表征。该特定目的旨在对MTBP的新功能进行全面评估，尤其是在骨肉瘤转移中。 目的1。表征由MTBP丢失引起的骨肉瘤。 目标2。用条件MTBP和/或p53基因敲除等位基因生成和表征小鼠，特别是在成骨细胞中。 目标3。分离MTBP相互作用的蛋白质。