mTOR and S6K1 Mediate Assembly of the Translation Preinitiation Complex through Dynamic Protein Interchange and Ordered Phosphorylation Events

Holz, Marina K.; Ballif, Bryan A.; Gygi, Steven P.; Blenis, John

doi:10.1016/j.cell.2005.10.024

Cited by 1,042 publications

(950 citation statements)

References 37 publications

Supporting

Mentioning

889

Contrasting

Unclassified

Order By: Relevance

“…The elimination of S6K expression by siRNA modestly decreased (20-30%) cyclin D1 expression. S6K associates with translation initiation complexes and phosphorylates eIF4B (Holz et al, 2005;Shahbazian et al, 2006), which might explain these observations. However, our study suggests that S6K is not a primary regulator of cyclin D1 expression: (i) rapamycin treatment eliminates S6K activity in HEK293 cells but does not affect cyclin D1 levels and (ii) elimination of 4E-BP1 is enough to abolish the effect of rapamycin on cyclin D1 expression.…”

Section: Discussionmentioning

confidence: 90%

Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1

2007

View full text Add to dashboard Cite

There is currently substantial interest in the regulation of cell function by mammalian target of rapamycin (mTOR), especially effects linked to the rapamycin-sensitive mTOR complex 1 (mTORC1). Rapamycin induces G 1 arrest and blocks proliferation of many tumor cells, suggesting that the inhibition of mTORC1 signaling may be useful in cancer therapy. In MCF7 breast adenocarcinoma cells, rapamycin decreases levels of cyclin D1, without affecting cytoplasmic levels of its mRNA. In some cell-types, rapamycin does not affect cyclin D1 levels, whereas the starvation for leucine (which impairs mTORC1 signaling more profoundly than rapamycin) does. This pattern correlates with the behavior of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1, an mTORC1 target that regulates translation initiation). siRNA-mediated knockdown of 4E-BP1 abrogates the effect of rapamycin on cyclin D1 expression and increases the polysomal association of the cyclin D1 mRNA. Our data identify 4E-BP1 as a key regulator of cyclin D1 expression, indicate that this effect is not mediated through the changes in cytoplasmic levels of cyclin D1 mRNA and suggest that, in some cell types, interfering with the amino acid input to mTORC1, rather than using rapamycin, may inhibit proliferation.

show abstract

Section: Discussionmentioning

confidence: 90%

Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1

2007

View full text Add to dashboard Cite

show abstract

“…We therefore searched for possible splicing targets of SF2/ASF in these two pathways and identified the pre-mRNAs of MNK2 and S6K1 as SF2/ASF splicing targets. Human RPS6KB1 encodes S6K1, a kinase that phosphorylates the small-subunit ribosomal protein S6 and regulates translation 29 . Only one human RPS6KB1 spliced mRNA has been reported, whereas the mouse gene has two isoforms (http:// www.ensembl.org/, version 29).…”

Section: Effects On Alternative Splicing Of Endogenous Targetsmentioning

confidence: 99%

The gene encoding the splicing factor SF2/ASF is a proto-oncogene

Karni

Stanchina

Lowe

et al. 2007

Nat Struct Mol Biol

815

968

View full text Add to dashboard Cite

Alternative splicing modulates the expression of many oncogene and tumor-suppressor isoforms. We have tested whether some alternative splicing factors are involved in cancer. We found that the splicing factor SF2/ASF is upregulated in various human tumors, in part due to amplification of its gene, SFRS1. Moreover, slight overexpression of SF2/ASF is sufficient to transform immortal rodent fibroblasts, which form sarcomas in nude mice. We further show that SF2/ASF controls alternative splicing of the tumor suppressor BIN1 and the kinases MNK2 and S6K1. The resulting BIN1 isoforms lack tumor-suppressor activity; an isoform of MNK2 promotes MAP kinase-independent eIF4E phosphorylation; and an unusual oncogenic isoform of S6K1 recapitulates the transforming activity of SF2/ASF. Knockdown of either SF2/ASF or isoform-2 of S6K1 is sufficient to reverse transformation caused by the overexpression of SF2/ASF in vitro and in vivo. Thus, SF2/ASF can act as an oncoprotein and is a potential target for cancer therapy.For about three-quarters of human genes, individual or partial exons can be included in or excluded from different versions of the mature messenger RNA by alternative splicing 1 . Many alternative splicing factors combinatorially affect this process to determine which mRNA isoforms will serve as the templates for protein synthesis in a given cell type, developmental stage or physiological state 2 .SR proteins are a family of RNA-binding proteins that are essential for splicing. They act at multiple steps of spliceosome assembly and function in both constitutive and regulated splicing. Some heterogeneous nuclear ribonucleoprotein (hnRNP) proteins, which rapidly associate with nascent transcripts, have been implicated in the repression of certain alternative splicing events 2 . hnRNP and SR proteins can have antagonistic effects on the alternative splicing of particular exons in several genes 2 . Both types of factor can bind directly to precursor (pre)-mRNA transcripts, eliciting changes in the alternative splicing of various pre-mRNA substrates in a concentration-dependent manner, both in vitro and in transfection experiments 3,4 . Thus, changes in the expression of these proteins can affect the Reprints and permissions information is available online at

show abstract

“…S6K1 is thought to be primarily responsible for translation of mRNA species containing 5 0 terminal oligopyrimidine tracts (Dennis et al, 1996;von Manteuffel et al, 1997), though this remains controversial (Tang et al, 2001;Stolovich et al, 2002). Both S6K1 and 4E-BP1/eIF4E pathways are related to translation (Holz et al, 2005). It is not clear how rapamycin inhibition of these two pathways results in inhibition of cell motility.…”

Section: Rapamycin Inhibition Of Cell Motility Via S6k1 and 4e-bp1mentioning

confidence: 99%

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

et al. 2006

View full text Add to dashboard Cite

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.

show abstract

mTOR and S6K1 Mediate Assembly of the Translation Preinitiation Complex through Dynamic Protein Interchange and Ordered Phosphorylation Events

Cited by 1,042 publications

References 37 publications

Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1

Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1

The gene encoding the splicing factor SF2/ASF is a proto-oncogene

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

Contact Info

Product

Resources

About