Regulation of Myc-Mediated Tumorigenesis

描述（由申请人提供）：c-Myc转录因子是细胞周期进展所必需的，是人类癌症（包括淋巴瘤）中最常见的过表达癌基因之一。由于Myc尚未被证明是一个合适的药物靶点，因此鉴定和表征调节Myc功能的蛋白质是非常需要和感兴趣的。Mdm2(2)结合蛋白（MTBP）在酵母- 2杂交中被鉴定为与Mdm2结合的蛋白，Mdm2是肿瘤抑制因子p53的调节因子。肿瘤细胞系的过表达研究表明，MTBP影响Mdm2 E3泛素连接酶活性，从而影响p53的表达。然而，与Mdm2缺失可通过p53缺失挽救的胚胎致死性相反，mtbp缺失的胚胎致死性并未因p53缺失而挽救。MTBP-和Mdm2缺陷小鼠之间的这一差异和其他差异表明，MTBP可能不调节Mdm2，我们的初步数据也不支持MTBP在Mdm2调节中的作用。具体来说，来自MTBP缺失小鼠的B细胞没有改变Mdm2的表达或功能，但确实减少了myc介导的增殖，并显著延缓了myc介导的B细胞淋巴瘤的发展。此外，小鼠和人类淋巴瘤表达MTBP水平升高。这些数据表明MTBP可能有助于myc诱导的淋巴瘤形成，并且这与Mdm2无关。质谱数据揭示了MTBP与蛋白的新关联，这些蛋白被报道调节Myc的转化和凋亡功能。总之，我们的数据为MTBP功能的新机制提供了见解，并揭示了Myc的潜在新调节因子。因此，本研究的目的是阐明MTBP的功能及其在myc诱导的B细胞淋巴瘤发生和进展中的作用。我们假设MTBP调节Myc的生长促进功能，从而促进Myc诱导的肿瘤发生。为了验证这一假设，我们提出了两个具体目标，每个目标都将利用多种互补方法。Aim 1的实验将评估MTBP调控Myc的生化机制。Aim 2的实验将确定MTBP是否具有致癌特性，以及MTBP在myc诱导的增殖、凋亡、转化和淋巴瘤细胞生长和进展中的需求和贡献。我们提出的研究将为myc诱导的淋巴瘤发展提供重要的新见解，并显著增加我们对MTBP在肿瘤发生中的作用的理解。我们的研究结果最终将导致改善非霍奇金淋巴瘤和70%的Myc过表达的人类恶性肿瘤的治疗干预策略。

DESCRIPTION (provided by applicant): The c-Myc transcription factor that is necessary for cell cycle progression is one of the most frequently overexpressed oncogenes in human cancer, including lymphoma. Since Myc has of yet not proven to be a suitable drug target, there is great need and interest in identifying and characterizing proteins that regulate Myc functions. Mdm2 (Two) Binding Protein (MTBP) was identified in a yeast-two-hybrid as a protein that bound to Mdm2, a regulator of the tumor suppressor p53. Overexpression studies in tumor cell lines showed MTBP influenced Mdm2 E3 ubiquitin ligase activity and consequently p53 expression. However, in contrast to the embryonic lethality of Mdm2 deletion that is rescued with p53 deletion, MTBP-null embryonic lethality was not rescued with loss of p53. This and other differences between MTBP- and Mdm2-deficient mice suggest that MTBP may not regulate Mdm2, and our preliminary data also does not support a role for MTBP in Mdm2 regulation. Specifically, B cells from mice deficient in MTBP did not have altered Mdm2 expression or function, but did have reduced Myc-mediated proliferation and a significant delay in Myc-mediated B cell lymphoma development. Moreover, murine and human lymphomas expressed increased levels of MTBP. These data suggest that MTBP may contribute to Myc-induced lymphomagenesis and that this is independent of Mdm2. Mass spectrometry data revealed a novel association of MTBP with proteins that are reported to modulate transforming and apoptotic functions of Myc. Together our data provide insight into a novel mechanism of MTBP function and uncovered a potentially novel regulator of Myc. Therefore the objective of this proposal is to elucidate MTBP function and its role in Myc-induced B cell lymphoma development and progression. We hypothesize that MTBP regulates the growth promoting functions of Myc and thereby contributes to Myc-induced tumorigenesis. To test this hypothesis, we propose two Specific Aims, each of which will utilize multiple complementary approaches. Experiments in Aim 1 will assess the biochemical mechanism of Myc regulation by MTBP. Experiments in Aim 2 will determine whether MTBP has oncogenic properties and the requirements and contribution of MTBP in Myc-induced proliferation, apoptosis, transformation, and lymphoma cell growth and progression. Our proposed studies will provide important new insights into Myc-induced lymphoma development and significantly increase our understanding of the role MTBP has in tumorigenesis. Results from our studies should ultimately lead to improved therapeutic intervention strategies for the treatment of non-Hodgkin's lymphoma and the 70% of human malignancies that overexpress Myc.