The serine/threonine protein kinase AKT, a downstream target of PI3K, is a positive regulator of mTOR activity [20]. PI3K regulates phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3, in turn, activates the 3-phosphoinositide-dependent protein kinase 1 (PDK1), which then activates AKT. The phosphatase and tensin homolog deleted on chromosome 10 gene (PTEN) counteracts PI3K in this BB-94 process by dephosphorylating PIP3, thereby preventing activation of AKT [21]. Phosphorylations at both sites of T308 and S473 are necessary for full AKT activation [22]. It is now clear that AKT upregulates mTOR by phosphorylating and inhibiting the activity of the tuberous sclerosis complex-2 (TSC2) [23], [24] and [25], thereby reducing GAP (GTPase-activating protein) activity of TSC2 towards Rheb (Ras homolog enriched in brain), a positive regulator of mTOR [26], [27] and [28].
In this study, we demonstrate that the mTOR signaling component 4EBP1, but not S6K, is participates in normal thymocyte development, and that deregulation of 4EBP1 and its targeting proteins c-Myc and cyclin D1 in Atm?/? thymocyte is critically involved in thymic lymphomagenesis in Atm deficient mice. Thus, our findings provide new clues linking ATM and mTOR to thymocyte development and to thymocyte tumorigenesis. These findings may lead to exploration of innovative strategies, such as targeting mTOR with rapamycin, to prevent lymphoid tumors in A-T patients.
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