Phosphorylation of the Translational Repressor PHAS-I by the Mammalian Target of Rapamycin

Brunn, Gregory J.; Hudson, Christine C.; Sekulić, Aleksandar; Williams, Josie M.; Hosoi, Hajime; Houghton, Peter J.; Lawrence, John C.; Abraham, Robert T.

doi:10.1126/science.277.5322.99

Cited by 871 publications

(704 citation statements)

References 28 publications

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“…This is in contrast to the situation in yeast where the factor disappears within 1 ± 2 h of rapamycin treatment (Berset et al, 1998). Another potential mechanism by which cycloheximide might destabilize eIF4G is by promoting the phosphorylation of the 4E-BPs via activation of the mTOR/p70 S6 kinase signalling pathway (Krieg et al, 1988;Brunn et al, 1997;Fadden et al, 1997;Lawrence and Abraham, 1997). This would have the e ect of dissociating eIF4E from the 4E-BPs and favouring its association with eIF4G (Graves et al, 1995;Von Manteu el et al, 1996;Brunn et al, 1997), thus potentially altering the conformation of the latter (Ohlmann et al, 1997).…”

Section: Discussionmentioning

confidence: 96%

“…Another potential mechanism by which cycloheximide might destabilize eIF4G is by promoting the phosphorylation of the 4E-BPs via activation of the mTOR/p70 S6 kinase signalling pathway (Krieg et al, 1988;Brunn et al, 1997;Fadden et al, 1997;Lawrence and Abraham, 1997). This would have the e ect of dissociating eIF4E from the 4E-BPs and favouring its association with eIF4G (Graves et al, 1995;Von Manteu el et al, 1996;Brunn et al, 1997), thus potentially altering the conformation of the latter (Ohlmann et al, 1997). However, to date, there is no evidence that the other inducers of apoptosis used in our studies impinge upon the mTOR signalling pathway and no reason to believe that the activation of this pathway would be a ected by caspase inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…However this interaction is inhibited by a small family of 4E binding proteins (4E-BPs) which can compete with eIF4G for binding to eIF4E Haghighat et al, 1995;Altmann et al, 1997;Matsuo et al, 1997). The extent of complex formation between the best studied of these proteins, 4E-BP1 (also known as PHAS-I) (Lawrence and , and eIF4E is regulated by the phosphorylation of 4E-BP1 (Graves et al, 1995;Von Manteu el et al, 1996;Brunn et al, 1997). This phosphorylation is activated by a pathway which can be inhibited by the macrolide immunosuppressant, rapamycin Von Manteu el et al, 1996;Beretta et al, 1996a;Fadden et al, 1997;Brunn et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…The extent of complex formation between the best studied of these proteins, 4E-BP1 (also known as PHAS-I) (Lawrence and , and eIF4E is regulated by the phosphorylation of 4E-BP1 (Graves et al, 1995;Von Manteu el et al, 1996;Brunn et al, 1997). This phosphorylation is activated by a pathway which can be inhibited by the macrolide immunosuppressant, rapamycin Von Manteu el et al, 1996;Beretta et al, 1996a;Fadden et al, 1997;Brunn et al, 1997). As a result rapamycin inhibits cap-dependent initiation (Beretta et al, 1996a,b), as well as antagonizing increases in protein synthesis brought about by mitogenic stimuli .…”

Section: Introductionmentioning

confidence: 99%

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Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

1998

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We have investigated the e ect of inducing apoptosis in BJAB and Jurkat cells on the cellular content of several polypeptide chain initiation factors. Serum deprivation results in inhibition of protein synthesis and induction of apoptosis in BJAB cells; at early times, there is selective degradation of polypeptide initiation factor eIF4G but no major losses of other key initiation factors. The disappearance of full length eIF4G is accompanied by the appearance of smaller forms of the protein, including a major product of approximately 76 kDa. Apoptosis induced by cycloheximide results in similar e ects. Both total cytoplasmic eIF4G and eIF4G associated with eIF4E are degraded with a half-life of 2 ± 4 h under these conditions. Treatment of serum-starved or cycloheximide-treated cells with Z-VAD.FMK or Z-DEVD.FMK, which inhibit caspases required for apoptosis, protects eIF4G from degradation and blocks the appearance of the ca. 76 kDa product. Exposure of BJAB cells to rapamycin rapidly inhibits protein synthesis but does not lead to acute degradation of eIF4G. In both BJAB and Jurkat cells induction of apoptosis with anti-Fas antibody or etoposide also results in the selective loss of eIF4G, which is inhibitable by Z-VAD.FMK. These data suggest that eIF4G is selectively targeted for cleavage as cells undergo apoptosis and is a substrate for proteases activated during this process.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

1998

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“…mTOR phosphorylates 4E-BP1 (Thr37/Thr46 and possibly Ser65 and Thr70) (MotheSatney et al, 2000;Gingras et al, 2001) and S6K1 (Thr389) (Dennis et al, 1996;von Manteuffel et al, 1997). Inhibition of mTOR by rapamycin results in hypophosphorylation of 4E-BP1 (Brunn et al, 1997;Mothe-Satney et al, 2000;Gingras et al, 2001). Subsequently, hypophosphorylated 4E-BP1 tightly binds to eIF4E, and prevents association of eIF4E with eIF4G and formation of the eIF4F initiation complex, thereby inhibiting cap-dependent translation of mRNA.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways

et al. 2006

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Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), inhibits tumor cell motility. However, the underlying mechanism is poorly understood. Here, we show that rapamycin inhibited type I insulin-like growth factor (IGF-I)-stimulated motility of a panel of cell lines. Expression of a rapamycin-resistant mutant of mTOR (mTORrr) prevented rapamycin inhibition of cell motility. However, cells expressing a kinase-dead mTORrr remained sensitive to rapamycin. Downregulation of raptor or rictor by RNA interference (RNAi) decreased cell motility. However, only downregulation of raptor mimicked the effect of rapamycin, inhibiting phosphorylation of S6 kinase 1 (S6K1) and 4E-BP1. Cells infected with an adenovirus expressing constitutively active and rapamycin-resistant mutant of p70 S6K1, but not with an adenovirus expressing wild-type S6K1, or a control virus, conferred to resistance to rapamycin. Further, IGF-I failed to stimulate motility of the cells, in which S6K1 was downregulated by RNAi. Moreover, downregulation of eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) by RNAi-attenuated rapamycin inhibition of cell motility. In contrast, expression of constitutively active 4E-BP1 dramatically inhibited IGF-I-stimulated cell motility. The results indicate that both S6K1 and 4E-BP1 pathways, regulated by TORC1, are required for cell motility. Rapamycin inhibits IGF-I-stimulated cell motility, through suppression of both S6K1 and 4E-BP1/eIF4E-signaling pathways, as a consequence of inhibition of mTOR kinase activity.

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Regulation of amino acid-sensitive TOR signaling by leucine analogues in adipocytes

et al. 2000

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In adipocytes, amino acids stimulate the target of rapamycin (TOR) signaling pathway leading to phosphorylation of the translational repressor, eIF-4E binding protein-I (4E-BP1), and ribosomal protein S6. L-leucine is the primary mediator of these effects. The structure-activity relationships of a putative L-leucine recognition site in adipocytes (LeuR(A)) that regulates TOR activity were analyzed by examining the effects of leucine analogues on the rapamycin-sensitive phosphorylation of the translational repressor, eIF-4E binding protein-I (4E-BP1), an index of TOR activity. Several amino acids that are structurally related to leucine strongly stimulated 4E-BP1 phosphorylation at concentrations greater than the EC(50) value for leucine. The order of potency was leucine > norleucine > threo-L-beta-hydroxyleucine approximately Ile > Met approximately Val. Other structural analogues of leucine, such as H-alpha-methyl-D/L-leucine, S-(-)-2-amino-4-pentenoic acid, and 3-amino-4-methylpentanoic acid, possessed only weak agonist activity. However, other leucine-related compounds that are known agonists, antagonists, or ligands of other leucine binding/recognition sites did not affect 4E-BP1 phosphorylation. We conclude from the data that small lipophilic modifications of the leucine R group and alpha-hydrogen may be tolerated for agonist activity; however, leucine analogues with a modified amino group, a modified carboxylic group, charged R groups, or bulkier aliphatic R groups do not seem to possess significant agonist activity. Furthermore, the leucine recognition site that regulates TOR signaling in adipocytes appears to be different from the following: (1) a leucine receptor that regulates macroautophagy in liver, (2) a leucine recognition site that regulates TOR signaling in H4IIE hepatocytes, (3) leucyl tRNA or leucyl tRNA synthetase, (4) the gabapentin-sensitive leucine transaminase, or (5) the system L-amino acid transporter.

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Phosphorylation of the Translational Repressor PHAS-I by the Mammalian Target of Rapamycin

Cited by 871 publications

References 28 publications

Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

Degradation of eukaryotic polypeptide chain initiation factor (eIF) 4G in response to induction of apoptosis in human lymphoma cell lines

Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways

Regulation of amino acid-sensitive TOR signaling by leucine analogues in adipocytes

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