Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by the formation of hamartomas in a wide range of human tissues. Mutation in either the TSC1 or TSC2 tumour suppressor gene is responsible for both the familial and sporadic forms of this disease. TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR). Furthermore, TSC2 is directly phosphorylated by Akt, which is involved in stimulating cell growth and is activated by growth stimulating signals, such as insulin. TSC2 is inactivated by Akt-dependent phosphorylation, which destabilizes TSC2 and disrupts its interaction with TSC1. Our data indicate a molecular mechanism for TSC2 in insulin signalling, tumour suppressor functions and in the inhibition of cell growth.

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Calcium signaling has been postulated to be critical for both heat and chilling tolerance in plants, but its molecular mechanisms are not fully understood. Here, we investigated the function of two closely related cyclic nucleotide-gated ion channel (CNGC) proteins, OsCNGC14 and OsCNGC16, in temperature-stress tolerance in rice (Oryza sativa) by examining their loss-of-function mutants generated by genome editing. Under both heat and chilling stress, both the cngc14 and cngc16 mutants displayed reduced survival rates, higher accumulation levels of hydrogen peroxide, and increased cell death. In the cngc16 mutant, the extent to which some genes were induced and repressed in response to heat stress was altered and some Heat Shock factor (HSF) and Heat Shock Protein (HSP) genes were slightly more induced compared to the wild type. Furthermore, the loss of either OsCNGC14 or OsCNGC16 reduced or abolished cytosolic calcium signals induced by either heat or chilling stress. Therefore, OsCNGC14 and OsCNGC16 are required for heat and chilling tolerance and are modulators of calcium signals in response to temperature stress. In addition, loss of their homologs AtCNGC2 and AtCNGC4 in Arabidopsis (Arabidopsis thaliana) also led to compromised tolerance of low temperature. Thus, this study indicates a critical role of CNGC genes in both chilling and heat tolerance in plants, suggesting a potential overlap in calcium signaling in response to high-and low-temperature stress.

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