Regulation of Myc-Mediated Tumorigenesis

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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.
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