A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dubé syndrome.

The mechanistic target of rapamycin complex 1 (mTORC1) is a key metabolic hub that controls the cellular response to environmental cues by exerting its kinase activity on multiple substrates. However, whether mTORC1 responds to diverse stimuli by differentially phosphorylating specific substrates is poorly understood. Here we show that transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy, is phosphorylated by mTORC1 via a substrate-specific mechanism that is mediated by Rag GTPases.

Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth.

The mechanistic target of rapamycin complex 1 (mTORC1) is recruited to the lysosome by Rag guanosine triphosphatases (GTPases) and regulates anabolic pathways in response to nutrients. We found that MiT/TFE transcription factors-master regulators of lysosomal and melanosomal biogenesis and autophagy-control mTORC1 lysosomal recruitment and activity by directly regulating the expression of RagD. In mice, this mechanism mediated adaptation to food availability after starvation and physical exercise and played an important role in cancer growth.

Up-regulation of miR-146b and down-regulation of miR-200b contribute to the cytotoxic effect of histone deacetylase inhibitors on ras-transformed thyroid cells.

Context: Histone deacetylase inhibitors (HDACis) are anticancer agents that inhibit tumor cell growth and/or survival. However, their mechanism of action remains largely undefined. Recently, we have demonstrated that HDACis induce apoptosis in a model of rat thyroid cells transformed by the v-ras-Ki oncogene (FRTL-5 v-ras-Ki).