The objective of this proposal is to determine how angiogenin (ANG)-induced transfer RNA (tRNA) cleavage facilitates tumor growth and survival. Our central hypothesis is that ANG-induced tRNA cleavage alters protein translation to enhance the expression of angiogenic, pro-growth and pro-survival proteins to promote tumorigenesis. This is based upon our own preliminary data showing that ANG selectively cleaves tRNAs to produce bioactive fragments (i.e., tiRNAs) that inhibit translation initiation. The rationale for te proposed research is that, once we know how tRNA cleavage re-programs protein translation, we will be able to modulate this event to treat cancer. We will test our central hypothesis by the completion of three specific aims:
AIM 1. Determine how YB-1 cooperates with tiRNAs to inhibit translation initiation in cancer cells. Our working hypothesis is that tiRNAs bind to the nucleic acid-binding cold shock domain of YB-1 to promote interactions with components of the translation initiation complex.
AIM 2. Determine how ANG-induced tRNA cleavage alters protein translation to augment the proliferation and survival of cancer cells. Our working hypothesis is that tiRNAs "activate" YB-1 to allow the preferential translation of internal ribosome entry site (IRSE) and upstream open reading frame (uORF)-containing transcripts encoding proteins that promote tumor cell growth and survival.
AIM 3. Determine the role of ANG-induced tRNA cleavage in tumorigenesis. Our working hypothesis is that tiRNAs act downstream of ANG to promote tumor growth. We will determine whether YB-1, an oncogene that targets the translational machinery to promote the epithelial- mesenchymal transition, partners with tRNA fragments to re-program protein translation in cancer cells. We will use non-biased gene array and candidate gene approaches to identify transcripts whose translation is modulated in response to tRNA cleavage. We will use siRNA knockdown to determine whether the ANG inhibitor RNH1 functions as a tumor suppressor protein. We will determine how the expression of tRNA fragments, YB-1 and RNH1 influence tumorigenesis in murine xenografts. Finally, we will determine whether tRNA cleavage serves as a prognostic biomarker for prostate cancer. The contribution of the proposed research will be to determine how the ribonuclease activity of ANG promotes the growth and survival of tumor cells. This contribution is significant because it provides a molecular basis for the development of pharmacologic strategies to prevent ANG-mediated tumor growth. The proposed research is innovative because it focuses on the direct target of ANG, its RNA substrates, and attempts to determine how tRNA cleavage promotes tumorigenesis.
This project will determine how angiogenin, an enzyme that cleaves tRNA, promotes the growth and survival of tumor cells. By uncovering the mechanism by which tRNA cleavage promotes tumorigenesis, we will identify targets for the development of a new class of drugs for the treatment of cancer.
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