Abstract
The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) has the ability to sense and integrate signals from a variety of sources, including intracellular nutrients and energy, growth factors, and cellular stresses. mTORC1 senses many of these signals through a small G protein switch involving the tuberous sclerosis complex (TSC) tumor suppressors, TSC1 and TSC2, and the Ras-related small G protein Rheb. Multi-site phosphorylation of the TSC2 protein downstream of distinct signaling pathways appears to account for much of mTORC1's signal-integrating capacity. Importantly, the two most commonly activated oncogenic signaling pathways in human cancers, the PI3K-Akt and Ras-Erk pathways, phosphorylate and inhibit TSC2 to activate mTORC1. Aberrant activation of mTORC1 through genetic and environmental effects on the upstream signaling network is a common molecular event in a large variety of pathological settings, including the majority of genetic tumor syndromes, sporadic cancers, and obesity. However, we are just beginning to understand the downstream consequences of mTORC1 activation in both normal and disease states. I will discuss our evidence suggesting that mTORC1 signaling might be a major molecular link between environmental influences, such as diet, and increased cancer risk. In addition, I will present our work on the role of mTORC1 as a key downstream effector of oncogenic signaling pathways that promotes anabolic cell growth and proliferation by altering the cellular metabolic program.
Citation Format: Brendan D. Manning. The nutrient-sensing mTOR pathway in cancer initiation and progression. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr PL03-01.
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