Lymphangioleiomyomatosis (LAM), a genetic disorder characterized by widespread lesions of smooth muscle-like LAM cells, induces cystic destruction of the lung leading to the loss of pulmonary function for which no therapy exists. LAM is associated with mutational inactivation of the tumor suppressors tuberous sclerosis complex 1 (TSC1) and TSC2; loss of TSC2, in particular, is correlated with disease severity and tumor growth. Our previous studies demonstrate that inactivating mutations in TSC2 constitutively stimulates S6K1 signaling pathway promoting LAM cell growth. Our new preliminary data show that TSC1 and TSC2 may have differential roles in regulating S6K1 signaling via differential activation of the mammalian target of rapamycin (mTOR)/Raptor and mTOR/Rictor pathways. We also found that LAM and TSC2-/- cells escape the anti-proliferative effects of interferon (IFNs) in vitro and in vivo due to the constitutive activation of S6K1 and loss of TSC2 function. In this application, we will test our hypothesis that loss of TSC1 and TSC2 results in LAM cell proliferation due to dysregulation of the two processes: cell growth by the activation of mTOR/Raptor-S6K1 and cell cycle progression by the activation of mTOR/Rictor-Rac1. The constitutive activation of the mTOR-S6K1 signaling pathway due to TSC1/TSC2 loss of function abrogates the anti-proliferative activities of IFNs.
In Aim 1, we will determine whether mTOR/Raptor-S6K1 and mTOR/Rictor- Rac1 are necessary and sufficient, to promote LAM cell growth and proliferation.
In Aim 2, we will define whether the loss of TSC1/TSC2 and the constitutive activation of S6K1 abrogate the anti-proliferative activities of IFNs in LAM, TSC1-/-, and TSC2-/- cells.
In Aim 3, we will examine the, in vivo, role of the constitutively activated S6K1 due to TSC1 or TSC2 loss on tumorigenesis, and establish the translational possibilities for the combined treatment of these tumors with rapamycin and IFNs. These studies will define the key cellular and molecular mechanisms by which the constitutive activation of S6K1 regulates LAM cell growth, and will provide insight into the therapeutic targets that may prevent or abrogate cell growth in LAM. ? ? ?
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