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

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 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.

mTOR and HIF-1α-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome

“…These results suggest that in this tumor model rapamycin may be having a cytostatic effect rather than a cytotoxic effect, consistent with observations in other tumor types (15). Activation of mTORC1 results in increased translation of a number of key downstream targets, including cyclin D1 and the hypoxia inducible factor 1 alpha gene (HIF-1␣) (17)(18)(19)(20). We examined the protein levels of cyclin D1 and HIF-1␣ in the stomachs and polyps of Lkb1ϩ/ϩ and Lkb1ϩ/Ϫ mice by western blot.…”

“…These substrates include proteins involved in the regulation of protein translation such as the p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1) (16). Among the mRNAs known to be translationally up-regulated by mTORC1 are a number of key progrowth proteins including cyclin D1, cyclin D3, Mcl-1, c-myc, and the hypoxia inducible factor 1 alpha (HIF-1␣) (17)(18)(19)(20)(21).…”

MEK drives cyclin D1 hyperelevation during geroconversion

“…Although MEK itself was required for hyperexpression of cyclin D1, MTOR had additional but not major roles in this phenomenon. Noteworthy, it has been reported that cyclin D1 can, in turn, further activate MTOR, 69 and vice versa inhibition of MTOR can decrease cyclin D1 levels, 60,67 establishing positive feedback between them.…”

“…MTORC1 can increase cyclin D1 expression via inactivation of eukaryotic initiation factor 4E-binding protein 1. 60,61,67,68 Previously, the MTOR was the only pathway known to be involved in acquiring classic markers of a senescent phenotype, including cyclin D1 accumulation. For the first time, we added an additional pathway, the MAPK pathway that is required, for the acquisition of at least one hallmark of senescence: hyperaccumulation of cyclin D1.…”

The role of mTORC1 pathway in intestinal tumorigenesis

“…mTORC1 inhibitors, in contrast, can suppress expression of HIF-1α and its target genes. [39][40][41] Although the precise mechanism of mTORC1 activation in the intestinal polyps remains to be investigated, our data exclude the involvement of the PI3K-Akt and Erk pathways, AMPK and the nutrient status. Instead, we found that expression of mTOR at the mRNA and protein levels was increased significantly in the polyps of Apc ∆716 mice.…”