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The tor pathway: a target for cancer therapy

The tor pathway: a target for cancer therapy Target of rapamycin (TOR) — an essential protein that is conserved in eukaryotes — directly or indirectly regulates the translation of ribosomal proteins and, in yeast, regulates ribosome biogenesis. TOR controls cap-dependent translation initiation through phosphorylating and inactivating eukaryotic initiation factor 4E binding proteins, which allows formation of the eIF4F complex that is required for translation initiation of mRNAs that have long structured 5′-untranslated regions. TOR functions as a sensor of mitogen, energy and nutritient levels, acting as a gatekeeper for cell-cycle progression from G1 to S phase. Pathways that regulate TOR signalling are complex and involve positive regulators such as AKT that phosphorylate and inactivate negative regulators such as tuberin (TSC2). Pathways upstream of TOR are frequently activated in cancer. This can be through increased activity of phosphatidylinositol-3-kinase–AKT or kinases that regulate TSC2, or through mutations that inactivate TSC proteins. The TOR pathway is also upregulated in many human cancers and oncogenic transformation might sensitize cells to TOR inhibitors. TOR therefore represents a novel therapeutic target. Rapamycin and its analogues are highly specific inhibitors of TOR and are now in Phase I–III oncology clinical trials. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Reviews Cancer Springer Journals

The tor pathway: a target for cancer therapy

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References (194)

Publisher
Springer Journals
Copyright
Copyright © 2004 by Nature Publishing Group
Subject
Biomedicine; Biomedicine, general; Cancer Research
ISSN
1474-175X
eISSN
1474-1768
DOI
10.1038/nrc1362
Publisher site
See Article on Publisher Site

Abstract

Target of rapamycin (TOR) — an essential protein that is conserved in eukaryotes — directly or indirectly regulates the translation of ribosomal proteins and, in yeast, regulates ribosome biogenesis. TOR controls cap-dependent translation initiation through phosphorylating and inactivating eukaryotic initiation factor 4E binding proteins, which allows formation of the eIF4F complex that is required for translation initiation of mRNAs that have long structured 5′-untranslated regions. TOR functions as a sensor of mitogen, energy and nutritient levels, acting as a gatekeeper for cell-cycle progression from G1 to S phase. Pathways that regulate TOR signalling are complex and involve positive regulators such as AKT that phosphorylate and inactivate negative regulators such as tuberin (TSC2). Pathways upstream of TOR are frequently activated in cancer. This can be through increased activity of phosphatidylinositol-3-kinase–AKT or kinases that regulate TSC2, or through mutations that inactivate TSC proteins. The TOR pathway is also upregulated in many human cancers and oncogenic transformation might sensitize cells to TOR inhibitors. TOR therefore represents a novel therapeutic target. Rapamycin and its analogues are highly specific inhibitors of TOR and are now in Phase I–III oncology clinical trials.

Journal

Nature Reviews CancerSpringer Journals

Published: May 1, 2004

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