Scientific Reports · 2017 · 32 citations · 52 references
Life SciencesCell BiologyMolecular BiologyApoptosisCell SignalingSignal TransductionApoptotic SignalingCancer Cell SignalingCell Cycle ControlDna Damage SignalingDna Damage-induced ApoptosisTumor Suppressor GenesApoptosis-inducing FactorDna Damage InductionDna Damage Response PathwaysG1 Cell-cycle ArrestMtorc1 SignalingP53-mediated Cell Cycle ArrestP53-mediated Cell-cycle ArrestTumor Suppressor P53
The SEA/GATOR complex is an essential regulator of the mTORC1 pathway. In mammals the GATOR1 complex is composed of the proteins DEPDC5, NPRL2 and NPRL3. GATOR1 serves as an mTORC1 inhibitor and activates the mTORC1-modulating RagA GTPase. However, several GATOR members have mTORC1 independent functions. Here we characterize mammalian cells overexpressing the GATOR1 component NPRL2. We demonstrate that, in the cells with active p53, ectopic expression of NPRL2 induces NOX2-dependent production of reactive oxygen species and DNA damage. Overexpressed NPRL2 accumulates in the nucleus, together with apoptosis-inducing factor (AIF). These events are accompanied by phosphorylation of p53, activation of a DNA-damage response and cell cycle arrest in G1 phase, followed by apoptosis. In the cells negative for active p53, NPRL2 ectopic expression leads to activation of CHK1 or CHK2 kinases and cell cycle arrest in S or G2/M phases. Combined, these results demonstrate a new role for the NPRL2, distinct from its function in mTORC1 regulation.
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