A Chemical Genetic Screen for mTOR Pathway Inhibitors Based on 4E-BP-Dependent Nuclear Accumulation of eIF4E

作者：Livingstone Mark; Larsson Ola; Sukarieh Rami; Pelletier Jerry; Sonenberg Nahum^*

来源：Chemistry & Biology, 2009, 16(12): 1240-1249.

DOI：10.1016/j.chembiol.2009.11.010

The signal transduction pathway wherein mTOR regulates cellular growth and proliferation is an active target for drug discovery. The search for new mTOR inhibitors has recently yielded a handful of promising compounds that hold therapeutic potential. This search has been limited by the lack of a high-throughput assay to monitor the phosphorylation of a direct rapamycin-sensitivem TOR substrate in cells. Here we describe a novel cell-based chemical genetic screen useful for efficiently monitoring mTOR signaling to 4E-BPs in response to stimuli. The screen is based on the nuclear accumulation of eIF4E, which occurs in a 4E-BP-dependent manner specifically upon inhibition of mTOR signaling. Using this assay in a small-scale screen, we have identified several compounds not previously known to inhibit mTOR signaling, demonstrating that this method can be adapted to larger screens.

• 出版日期2009-12-24