Table 1.
Circadian mTOR signaling in various tissues.
| Tissue | mTOR cascade components | Temporal activity pattern | Regulation or function | Reference |
|---|---|---|---|---|
| Mouse SCN | S6K1, S6, 4E-BP1 | Activated by light at early and late subjective night but not during the day | Modulates photic entrainment of SCN clock | Cao et al., 2008, 2010 |
| Human osteosarcoma | mTOR | N.D. | Knockdown leads to longer circadian period | Zhang et al., 2009 |
| Drosophila ventral lateral neurons | AKT, PTEN, RHEB, TSC, TOR, S6K | N.D. | Overexpression of TOR-S6K signaling lengthens circadian period; Akt hypomorphic mutants have a shorter circadian period | Zheng and Sehgal, 2010 |
| Mouse SCN | S6 | High at mid to late subjective day, peak at CT4-CT12 | Colocalize with cellular Per1 but not Per2 transcription | Cao et al., 2011 |
| Mouse liver | S6, 4E-BP1 | High at night, low during day | Rhythmical translation of mRNAs involved in ribosome biogenesis | Jouffe et al., 2013 |
| Mouse SCN | 4E-BP1 | High at late subjective day, early subjective night | Rhythmical translation of Vip mRNA, promoting SCN cell synchronization | Cao et al., 2013 |
| Mouse skeletal muscles | S6, AKT | Low at ZT5, high at ZT21-ZT1 | Regulated by fasting | Shavlakadze et al., 2013 |
| Chicken retina | mTOR, S6K1, S6 | High at late subjective day | Circadian regulation of protein level and functionality of L-type voltage-gated calcium channels in the retina | Huang et al., 2013 |
| Mouse frontal cortex, heart | S6K1, S6 | Frontal cortex: p-S6K1 is high at night Heart: p-S6 is high at late night and early day | N.D. | Khapre et al., 2014 |
| Mouse renal cell carcinoma | mTOR, S6K1 | High at night, low during day | Rhythmic mTOR activity influences the antitumor effect of mTOR inhibitors | Okazaki et al., 2014 |
| Mouse hippocampus | 4E-BP1, S6, AKT, mTOR | High during the day, low at night | Implicated in memory persistence | Saraf et al., 2014 |
| Mouse liver and fibroblasts | S6K1, S6, | High at night, low during day | S6K1 rhythmically associates with and phosphorylates BMAL1 at S42; phosphorylation at Ser42 is important for its translational function | Lipton et al., 2015 |
| Mouse adipose tissue | Rictor | Rictor and mTOR mRNA levels are high during the day and low at night | mRNA expression levels of core clock genes during the day are altered by Rictor conditional knockout; animals show higher blood pressure at night | Drägert et al., 2015a,b |
| Mouse arcuate nucleus | p-S6(Ser235/236), p-4E-BP1(Thr37/46); Raptor | High at early night, low at early day | Raptor knockout in agouti-related protein/neuropeptide Y (Agrp/NPY) neurons abolishes circadian expression of Agrp and NPY mRNAs | Albert et al., 2015 |
| Rat cardiac and skeletal muscles | mTOR, S6K1 | High during the day, low at night | N.D. | Chang et al., 2016 |
| Drosophila brain | TOR | Highest at ZT20 and lowest at ZT4 | Silencing of TOR in per expressing cells shortens circadian period of fly locomotor activity rhythms | Kijak and Pyza, 2017 |
| Mouse brain and MEFs | TSC1 and TSC2 | N.D. | mTOR regulates BMAL1 translation, degradation, and subcellular localization. Mouse models of TSC show high BMAL1 level and abnormal circadian rhythms | Lipton et al., 2017 |
| Human breast cancer cell line MCF-7 | p-S6(Ser240/244) | High from 12 to 24 h after serum shock | Delivery of Everolimus during 0∼24 h after serum shock induces a more evident G0/G1 blockage compared to delivery during 12∼36 h. Inhibition of mTOR activity reduces Cyclin D1 and Cyclin D3 protein levels | Zhang et al., 2018 |
| Mouse SCN, liver, fibroblasts, hepatocytes, and lipocytes | mTOR, S6,4E-BP1 | High at night, low during the day in liver | mTOR inhibition lengthens circadian period and damps amplitude, whereas mTOR activation shortens period and augments amplitude | Ramanathan et al., 2018 |
| Neurospora crassa | NCU05950, homologous to the TOR pathway protein LAMTOR1 (mammals) | Arrhythmicity in NCU05950 protein levels | Anchored to the outer vacuolar membrane; mutation compromises FRQ-less rhythms | Ratnayake et al., 2018 |
| Several human and mouse cell lines | mTORC1, p-4E-BP1, and p-S6K1 | Rhythmic in normoxia buffer, amplitude, and phase changed in hypoxia buffer | Acidification of cells suppresses mTORC1 signaling and circadian rhythmicity. Restoring mTORC1 signaling by knockdown of 4E-BP1 partially rescues clock oscillation | Walton et al., 2018 |