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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 G1 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 knock-down 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.Oncogene (2008) 27, 1106–1113; doi:10.1038/sj.onc.1210715; published online 27 August 2007 [ABSTRACT FROM AUTHOR]

There is currently a high level of interest in signalling through the mammalian target of rapamycin (mTOR). This reflects both its key role in many cell functions and its involvement in disease states such as cancers. The best understood targets for mTOR signalling are proteins involved in controlling the translational machinery, including the ribosomal protein S6 kinases and proteins that regulate the initiation and elongation phases of translation. Indeed, there is compelling evidence that at least one of these targets of mTOR (eukaryotic initiation factor eIF4E) plays a key role in tumorigenesis. It is regulated through the mTOR-dependent phosphorylation of inhibitory proteins such as eIF4E-binding protein 1. Thus, targeting mTOR signalling may be an effective anticancer strategy, in at least a significant subset of tumours. Not all effects of mTOR are sensitive to the classical anti-mTOR drug rapamycin, and this compound also interferes with other processes besides eIF4E function. Developing new approaches to targeting mTOR for cancer therapy requires more detailed knowledge of signalling downstream of mTOR. Such advances are likely to come from further work to understand the regulation of mTOR targets such as components of the translational apparatus.Oncogene (2006) 25, 6423–6435. doi:10.1038/sj.onc.1209887 [ABSTRACT FROM AUTHOR]