Regulation of Myc-Mediated Tumorigenesis

描述（由申请方提供）：细胞周期进展所必需的c-Myc转录因子是人类癌症（包括淋巴瘤）中最常过表达的癌基因之一。由于Myc尚未被证明是合适的药物靶点，因此对鉴定和表征调节Myc功能的蛋白质存在极大的需求和兴趣。Mdm 2（Two）Binding Protein（MTBP）是在酵母双杂交中鉴定的一种与肿瘤抑制因子p53的调节因子Mdm 2结合的蛋白质。肿瘤细胞系中的过表达研究表明MTBP影响Mdm 2 E3泛素连接酶活性，从而影响p53表达。然而，与用p53缺失挽救的Mdm 2缺失的胚胎致死性相反，MTBP无效的胚胎致死性不能用p53缺失挽救。MTBP和Mdm 2缺陷小鼠之间的这种差异和其他差异表明MTBP可能不调节Mdm 2，我们的初步数据也不支持MTBP在Mdm 2调节中的作用。具体而言，MTBP缺陷小鼠的B细胞没有改变Mdm 2表达或功能，但确实降低了Myc介导的增殖，并显著延迟了Myc介导的B细胞淋巴瘤的发展。此外，鼠和人淋巴瘤表达MTBP水平增加。这些数据表明，MTBP可能有助于Myc诱导的淋巴瘤发生，这是独立的Mdm 2。质谱数据揭示了MTBP与据报道调节Myc转化和凋亡功能的蛋白质的新关联。总之，我们的数据提供了对MTBP功能的新机制的深入了解，并发现了Myc的潜在新调节剂。因此，本研究的目的是阐明MTBP的功能及其在Myc诱导的B细胞淋巴瘤发生和发展中的作用。我们假设MTBP调节Myc的生长促进功能，从而有助于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的目标，每一个都将利用多种互补的方法。目的1中的实验将评估MTBP调节Myc的生化机制。目的2中的实验将确定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，并显着增加我们对MTBP在肿瘤发生中的作用的理解。我们的研究结果最终将改善非霍奇金淋巴瘤和70%过表达Myc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.