A Putative Sirolimus (Rapamycin) Effector Protein

Chen, Yanqiu; Chen, Huihong; Rhoad, A.; Warner, L.; Caggiano, Thomas J.; Failli, Amedeo; Zhang, Hongzhi; Hsiao, Chu-Lia; Nakanishi, Koji; Molnar-Kimber, Katherine L.

doi:10.1006/bbrc.1994.2140

Cited by 72 publications

(31 citation statements)

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“…Consistent with contacts predicted by the structure of the mTOR/rapamycin/FKBP complex (Chen et al, 1994;Stan et al, 1994;Choi et al, 1996) and with data from yeast, mutation of Ser2035 in the FRB domain of mTOR (analogous to serines 1972 and 1975 in Tor1 and Tor2, respectively) confers resistance to the known cellular and biochemical effects of rapamycin Brunn et al, 1997). While rapamycin inhibits the rate of cell cycle progression and proliferation of mammalian cells via inhibition of mTOR, as it does in yeast, for reasons that are not currently understood, the potency of rapamycinmediated cell cycle inhibition in mammalian cells varies widely among cell types.…”

Section: Discovery Of Rapamycin and Identification Of Torsupporting

confidence: 77%

“…Subsequent biochemical studies in mammalian cells led to the identification and cloning of the mammalian target of rapamycin, mTOR, from human, rat, and mouse. Since several groups cloned the gene at about the same time, TOR is also known as FRAP (FKBP12-rapamcyin-associated protein), RAFT (rapamycin and FKBP12 target), RAPT (rapamycin target), or SEP (sirolimus effector protein) (Brown et al, 1994;Chen et al, 1994;Chiu et al, 1994;Sabatini et al, 1995;Sabers et al, 1995). TOR is a large (290 kDa) evolutionarily conserved member of the phosphatidylinositol 3-kinase (PI3K)-kinase-related kinase (PIKK) superfamily in which a COOH-terminal kinase domain with lipid kinase homology functions as a serine/ threonine protein kinase (reviewed in Keith and Schreiber, 1995).…”

Section: Discovery Of Rapamycin and Identification Of Tormentioning

confidence: 99%

“…ATM, ATR, and DNA-PK) are similarly large and appear to function in cell cycle checkpoint control (reviewed in Keith and Schreiber, 1995), consistent with the function of TOR in a nutrient-sensitive cell cycle checkpoint. In contrast to yeast species, which contain two TOR homologs (Tor1 and Tor2) (Helliwell et al, 1994), only one TOR ortholog has been identified in higher eukaryotes, including mammals, flies, and worms (Brown et al, 1994;Chen et al, 1994;Chiu et al, 1994;Sabatini et al, 1995;Sabers et al, 1995;Oldham et al, 2000;Zhang et al, 2000;Long et al, 2002).…”

Section: Discovery Of Rapamycin and Identification Of Tormentioning

confidence: 99%

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Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

2004

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Cell growth (an increase in cell mass and size through macromolecular biosynthesis) and cell cycle progression are generally tightly coupled, allowing cells to proliferate continuously while maintaining their size. The target of rapamycin (TOR) is an evolutionarily conserved kinase that integrates signals from nutrients (amino acids and energy) and growth factors (in higher eukaryotes) to regulate cell growth and cell cycle progression coordinately. In mammals, TOR is best known to regulate translation through the ribosomal protein S6 kinases (S6Ks) and the eukaryotic translation initiation factor 4E-binding proteins. Consistent with the contribution of translation to growth, TOR regulates cell, organ, and organismal size. The identification of the tumor suppressor proteins tuberous sclerosis1 and 2 (TSC1 and 2) and Ras-homolog enriched in brain (Rheb) has biochemically linked the TOR and phosphatidylinositol 3-kinase (PI3K) pathways, providing a mechanism for the crosstalk that occurs between these pathways. TOR is emerging as a novel antitumor target, since the TOR inhibitor rapamycin appears to be effective against tumors resulting from aberrantly high PI3K signaling. Not only may inhibition of TOR be effective in cancer treatment, but rapamycin is an FDA-approved immunosuppressive and cardiology drug. We review here what is known (and not known) about the function of TOR in cellular and animal physiology.

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Section: Discovery Of Rapamycin and Identification Of Torsupporting

confidence: 77%

Section: Discovery Of Rapamycin and Identification Of Tormentioning

confidence: 99%

Section: Discovery Of Rapamycin and Identification Of Tormentioning

confidence: 99%

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Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

2004

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“…A single mammalian TOR protein has been cloned from several species, and alternatively termed mTOR, FRAP (FKBP12 and rapamycin associated protein), RAFT (rapamycin and FKBP12 target), SEP (sirolimus effector protein), or RAPT (rapamycin target; refs. [23][24][25][26][27]. Here, we refer to the mammalian protein as mTOR.…”

Section: Rapamycin and Tormentioning

confidence: 99%

The target of rapamycin (TOR) proteins

Raught

Gingras

Sonenberg

2001

Proc. Natl. Acad. Sci. U.S.A.

559

437

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Rapamycin potently inhibits downstream signaling from the target of rapamycin (TOR) proteins. These evolutionarily conserved protein kinases coordinate the balance between protein synthesis and protein degradation in response to nutrient quality and quantity. The TOR proteins regulate (i) the initiation and elongation phases of translation, (ii) ribosome biosynthesis, (iii) amino acid import, (iv) the transcription of numerous enzymes involved in multiple metabolic pathways, and (v) autophagy. Intriguingly, recent studies have also suggested that TOR signaling plays a critical role in brain development, learning, and memory formation. Rapamycin Inhibits Long-Term FacilitationS ynaptic plasticity, the capacity of neurons to modulate the strength of synaptic connections, is believed to be critical for learning and memory formation. Long-term synaptic plasticity (necessary for the formation of long-term memory) requires alterations in gene expression and the establishment of new synaptic connections (1-3). These findings presented an interesting dilemma: That is, how can changes in gene expression in the cell body alter the strength of individual synaptic connections? Recent data suggest that stimulated synapses are ''tagged'' to capture mRNAs produced in the soma and exported throughout the cell (4). Synaptic tagging thus results in localization of mRNAs only to those synapses marked by previous activity. This model also presupposes that long-term plasticity depends on local translation of the localized mRNAs. Indeed, ribosomes, tRNAs, translation initiation factors, and translation elongation factors are found in dendrites (5, 6), and protein synthesis has been demonstrated to occur in isolated synaptic bodies (7,8). Functional studies have demonstrated that protein synthesis is required for potentiation of synaptic transmission elicited by neurotrophic factors in hippocampal slices (9), and for the establishment of long-term facilitation in Aplysia neurons (10). Kandel and coworkers implicated a specific intracellular signaling pathway in this process by demonstrating that serotoninstimulated synaptic protein synthesis can be blocked with rapa-

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“…One well described signaling intermediate in the mTOR pathway is p70 S6 kinase (51,52). By inhibiting mTOR, rapamycin mimics growth-factor withdrawal, characterized by inhibition of protein synthesis and inhibition of cell cycle progression at the G 1 -S transition (53,54).…”

mentioning

confidence: 99%