mTOR Regulates Cell Proliferation
Cyclins are proteins that regulate the activity of enzymes called cyclin-dependent kinases (CDKs), which, in turn, regulate the progression of cells through the cell cycle.
A primary way that mTOR exerts its regulatory effects on cell proliferation is by controlling the production of cyclin D1, which controls CDKs 4 and 6—the CDKs that regulate the passage of cells through the critical G1-S restriction point of the cell cycle. Recently, cyclin D1 has been shown to play a role in gene transcription, cell metabolism, and cell migration as well.1-3
The role of mTOR in cell proliferation.
In many cancers, mTOR is inappropriately "switched on" due to the abnormal activation of one or more of the upstream signaling pathways that regulate mTOR activity. As a result, cyclin D1 is overexpressed. Cyclin D1 overexpression had been associated with a number of cancers, including breast cancer, colon cancer, prostate cancer, lymphoma, and melanoma.3
Activated mTOR may also play an additional role in cell cycle progression in cancer cells that have been treated with DNA-damaging agents, such as platinum drugs. For the DNA damage in these cells to be repaired, the cell cycle must first be stopped. mTOR controls the production of p21, the regulatory protein that stops the cell cycle so that the damage can be repaired. Inhibiting mTOR activation has been shown to inhibit production of p21, increasing the likelihood that damage caused by DNA-damaging agents will prove lethal to cancer cells.4
References:
- Rosenwald IB, Kaspar R, Rousseau D, et al. Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels. J Biol Chem. 1995;270:21176-21180.
- Nelsen CJ, Rickheim DG, Tucker MM, Hansen LK, Albrecht JH. Evidence that cyclin D1 mediates both growth and proliferation downstream of TOR in hepatocytes. J Biol Chem. 2003;278:3656-3663.
- Fu M, Wang C, Li Z, Sakamaki T, Pestell RG. Minireview: cyclin D1: normal and abnormal functions. Endocrinology. 2004;145:5439-5447.
- Beuvink I, Boulay A, Fumagalli S, et al. The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of P21 translation. Cell. 2005;120:747-759.
