2005
DOI: 10.1128/mcb.25.7.2558-2572.2005
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Distinct Signaling Events Downstream of mTOR Cooperate To Mediate the Effects of Amino Acids and Insulin on Initiation Factor 4E-Binding Proteins

Abstract: Signaling through the mammalian target of rapamycin (mTOR) controls cell size and growth as well as other functions, and it is a potential therapeutic target for graft rejection, certain cancers, and disorders characterized by inappropriate cell or tissue growth. mTOR signaling is positively regulated by hormones or growth factors and amino acids. mTOR signaling regulates the phosphorylation of several proteins, the best characterized being ones that control mRNA translation. Eukaryotic initiation factor 4E-bi… Show more

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Cited by 198 publications
(220 citation statements)
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“…To determine whether binding of 4E-BP1 to eIF4E does indeed regulate cyclin D1 expression, we overexpressed two forms of 4E-BP1 in HEK293 cells: a wild-type 4E-BP1 and a mutant (AAAA/F113A), which is mutated in both the RAIP and the TOS motifs. This mutant cannot be phosphorylated and binds 'constitutively' to eIF4E (Tee and Proud, 2002;Wang et al, 2005). Similar levels of eIF4E/4E-BP1 complexes were seen in serum-grown cells expressing the two different 4E-BP1 species (Figure 3a).…”
Section: Resultsmentioning
confidence: 58%
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“…To determine whether binding of 4E-BP1 to eIF4E does indeed regulate cyclin D1 expression, we overexpressed two forms of 4E-BP1 in HEK293 cells: a wild-type 4E-BP1 and a mutant (AAAA/F113A), which is mutated in both the RAIP and the TOS motifs. This mutant cannot be phosphorylated and binds 'constitutively' to eIF4E (Tee and Proud, 2002;Wang et al, 2005). Similar levels of eIF4E/4E-BP1 complexes were seen in serum-grown cells expressing the two different 4E-BP1 species (Figure 3a).…”
Section: Resultsmentioning
confidence: 58%
“…However, there was little change in the overall phosphorylation of Thr37/46, which is rather insensitive to rapamycin (Wang et al, 2005).…”
Section: Resultsmentioning
confidence: 90%
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“…*p<0.05 for difference from non-induced controls. Experiments were repeated three times with similar results Induction of DN-HNF1A is associated with an increase in p27 mRNA and protein levels Inhibition of mTORC1 signalling leads to the hypophosphorylation of 4E-BP1 and enhanced binding to eIF4E, blocking cap-dependent translation and causing cell-cycle arrest at G1 [29]. Most eukaryotic mRNAs are translated through a cap-dependent mechanism of initiation.…”
Section: Ins-1 Cells Inducibly Expressing Dn-hnf1a But Not Wt-mentioning
confidence: 86%
“…Reports that deprivation of growth factors or amino acids, and subsequent rapamycin treatment, represses T37/46 phosphorylation also supports this binding affinity model. 10,11 This fundamental difference in substrate affinity may also account for why long-term rapamycin treatment recovers 4E-BP1 but not S6K1 phosphorylation. As mTORC1 readjusts its structure, 4E-BP1 consequently recovers in phosphorylation, but not S6K1.…”
Section: Implications For Rapamycin-based Cancer Therapymentioning
confidence: 99%