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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
Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1
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 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.
rapamycin, translation initiation, 4E-BP1, cell cycle, cancer
0950-9232
1106-1113
Averous, J.
a0ddbb49-2564-4d1c-9f85-5b651b456bd2
Fonseca, B.D.
daa8fb54-d75f-444b-b7d4-722925dfcaf5
Proud, C.G.
c2cc50f9-4565-4d59-9dfc-aa70b9268a6e
Averous, J.
a0ddbb49-2564-4d1c-9f85-5b651b456bd2
Fonseca, B.D.
daa8fb54-d75f-444b-b7d4-722925dfcaf5
Proud, C.G.
c2cc50f9-4565-4d59-9dfc-aa70b9268a6e

Averous, J., Fonseca, B.D. and Proud, C.G. (2008) Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1. Oncogene, 27 (8), 1106-1113. (doi:10.1038/sj.onc.1210715). (PMID:17724476)

Record type: Article

Abstract

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 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.

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e-pub ahead of print date: 27 August 2007
Published date: 14 February 2008
Keywords: rapamycin, translation initiation, 4E-BP1, cell cycle, cancer
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 350181
URI: https://eprints.soton.ac.uk/id/eprint/350181
ISSN: 0950-9232
PURE UUID: 8b811c3e-29a1-43c1-82ad-574d73727659

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Date deposited: 19 Mar 2013 11:36
Last modified: 16 Jul 2019 21:40

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