Project 2: LKB1/AMPK signaling and Peutz-Jeahers syndrome.The focus of this project is to further elucidate the signal transduction pathways that inhibithamartomas formation in humans, focusing on the recently discovered role of the LKB1 tumorsuppressor in regulating mTOR signaling via the TSC proteins. The LKB1 tumor suppressor is aserine/threonine kinase which directly phosphorylates and activates the AMP-activated proteinkinase (AMPK). Through its regulation of AMPK, LKB1 serves as an low energy checkpoint thatcontrols the response of normal cells and tumor cells to conditions of low glucose and low oxygen.We previously showed this effect is due in part to AMPK induced activation of the TSC2 tumorsuppressor and subsequent inhibition of mTOR signaling. We speculate that loss of this normalcheckpoint on cell growth is not only critically disrupted in hamartomas, but also in a variety ofsporadic tumors. Finally, we have found that cells lacking the LKB1/AMPK/TSC2 pathway areuniquely sensitized to apoptosis following energy deprivation. We anticipate that therapeuticinterventions exploiting these findings will be of broad utility, given that agents which confer thoseeffects are already in widespread clinical use as anti-diabetic modalities.
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