The ARF tumor suppressor is frequently mutated or downregulated in cancer. The major role of ARF is to activate p53 by sequestering the p53 regulator Mdm2. ARF also plays a significant role in ribosome biogenesis and mRNA translation. Previously, loss of Arf has been shown to cause a bulk increase in ribosome biogenesis, ribosome export into the cytoplasm and an increase in global protein synthesis. Activation of ARF inhibits these processes. Notably, ARF is known to specifically regulate the translation of several mRNAs. Based on previously published data we hypothesize that ARF regulates the translation of IRES containing mRNAs through displacement of RpL11 from the ribosome. To address our hypothesis, we propose three aims: 1) To map global translational regulation upon ARF loss or gain using ribosome profiling. 2) To assess the regulation of IRES containing mRNAs by ARF. 3) To identify proteins involved in ARF- dependent translational reprogramming
Tumor cells have a requirement for increased protein synthesis to meet the demands of rapid growth. Understanding the mechanisms of translational reprogramming that allow for increased and selective protein synthesis could lead to new avenues for therapeutics.
