| Fox0O transcription factors and the target of rapamycin complex 1(TORC1) are conserved downstream effectors of Akt. Here we unraveled regulatory circuits underlying interplay between Akt, FoxO, and mTOR.;Activated FoxO1 inhibits mTORC1 by TSC-dependent and TSC-independent mechanisms. First, FoxO1 binds the promoter region of Sestrin3 (Sesn3) gene and markedly and directly elevates Sesn3 expression, which in turn inhibits mTORC1 activity in TSC wild-type cells. Second, FoxO1 markedly elevates the expression of Rictor leading to increased mTORC2 activity that consequently activates Akt. In TSC2-deficient cells, the elevation of Rictor increases mTORC2 assembly therefore activating mTORC2 and Akt. Moreover, elevated Rictor can inhibit mTORC1 activity.;Thus FoxO may act as rheostat that maintains homeostatic balance between Akt and mTOR complexes activities. We hypothesize and prove that in certain conditions for example growth factor restriction and oxidative stress, FoxO transiently activating Akt, thereby increases insulin and growth factor sensitivity, while transiently inhibiting mTORC1, thereby obtains overall control of FoxO-mediated biological functions which are usually oppositely regulated by mTORC1 activity. |
