The long-term goal of this project is to determine the mechanism(s) by which c-Myc regulates angiogenesis, and how Myc induced regulation of angiogenesis contributes to tumor development. Myc's ability to induce Vegf, which is critical to angiogenesis, appears to be due to effects of Myc on stabilizing Vegf RNA, rather than through directly targeting its transcription. Myc is able to activate the expression of many AUBPs and to repress others, in particular Tristetraprolin (TTP), which have important roles in controlling the stability of many mRNAs, including Vegf. This grant focuses on the role of TTP to explore in its importance in Myc-induced angiogenesis and lymphomagenesis. The promoter region of TTP harbors five initiator elements through which Myc is known to repress transcription, suggesting that its transcription is directly repressed by Myc.
Specific Aim 1 will identify whether or not TTP is directly repressed by Myc.
Specific Aim 2 will determine if Myc mediated repression of TTP is necessary for Myc-induced angiogenesis and lymphomagenesis by assessing the effects of enforced TTP expression in general and, more specifically in combination with Myc, to determine if Myc must repress TTP to provoke tumor angiogenesis and lymphoma development.
Specific Aim 3 will assess the effects of TTP loss on the Myc response; to test whether TTP loss augments Myc's ability to induce angiogenesis and lymphomagenesis.
| Rounbehler, Robert J; Fallahi, Mohammad; Yang, Chunying et al. (2012) Tristetraprolin impairs myc-induced lymphoma and abolishes the malignant state. Cell 150:563-74 |
| Rounbehler, Robert J; Li, Weimin; Hall, Mark A et al. (2009) Targeting ornithine decarboxylase impairs development of MYCN-amplified neuroblastoma. Cancer Res 69:547-53 |
