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

Avérous, Julien; Fonseca, Bruno D.; Proud, Christopher G.

doi:10.1038/sj.onc.1210715

Cited by 179 publications

(136 citation statements)

References 30 publications

Supporting

Mentioning

118

Contrasting

Unclassified

Order By: Relevance

“…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.…”

Section: Rapamycin Reduces Tumor Burden and Proliferation In Lkb1؉/؊ supporting

confidence: 64%

“…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).…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Shackelford

Vasquez

Corbeil

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

189

161

View full text Add to dashboard Cite

Peutz-Jeghers syndrome (PJS) is a familial cancer disorder due to inherited loss of function mutations in the LKB1/ STK11 serine/ threonine kinase. PJS patients develop gastrointestinal hamartomas with 100% penetrance often in the second decade of life, and demonstrate an increased predisposition toward the development of a number of additional malignancies. Among mitogenic signaling pathways, the mammalian-target of rapamycin complex 1 (mTORC1) pathway is hyperactivated in tissues and tumors derived from LKB1-deficient mice. Consistent with a central role for mTORC1 in these tumors, rapamycin as a single agent results in a dramatic suppression of preexisting GI polyps in LKB1؉/؊ mice. However, the key targets of mTORC1 in LKB1-deficient tumors remain unknown. We demonstrate here that these polyps, and LKB1-and AMPK-deficient mouse embryonic fibroblasts, show dramatic up-regulation of the HIF-1␣ transcription factor and its downstream transcriptional targets in an rapamycin-suppressible manner. The HIF-1␣ targets hexokinase II and Glut1 are up-regulated in these polyps, and using FDG-PET, we demonstrate that LKB1؉/؊ mice show increased glucose utilization in focal regions of their GI tract corresponding to these gastrointestinal hamartomas. Importantly, we demonstrate that polyps from human PeutzJeghers patients similarly exhibit up-regulated mTORC1 signaling, HIF-1␣, and GLUT1 levels. Furthermore, like HIF-1␣ and its target genes, the FDG-PET signal in the GI tract of these mice is abolished by rapamycin treatment. These findings suggest a number of therapeutic modalities for the treatment and detection of hamartomas in PJS patients, and potential for the screening and treatment of the 30% of sporadic human lung cancers bearing LKB1 mutations.AMPK ͉ FDG-PET ͉ glycolysis ͉ hamartoma ͉ polyposis

show abstract

Section: Rapamycin Reduces Tumor Burden and Proliferation In Lkb1؉/؊ supporting

confidence: 64%

mentioning

confidence: 99%

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

Shackelford

Vasquez

Corbeil

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

189

161

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

MEK drives cyclin D1 hyperelevation during geroconversion

2013

View full text Add to dashboard Cite

When the cell cycle becomes arrested, MTOR (mechanistic Target of Rapamycin) converts reversible arrest into senescence (geroconversion). Hyperexpression of cyclin D1 is a universal marker of senescence along with hypertrophy, beta-Gal staining and loss of replicative/regenerative potential (RP), namely, the ability to restart proliferation when the cell cycle is released. Inhibition of MTOR decelerates geroconversion, although only partially decreases cyclin D1. Here we show that in p21-and p16-induced senescence, inhibitors of mitogen-activated/extracellular signal-regulated kinase (MEK) (U0126, PD184352 and siRNA) completely prevented cyclin D1 accumulation, making it undetectable. We also used MEL10 cells in which MEK inhibitors do not inhibit MTOR. In such cells, U0126 by itself induced senescence that was remarkably cyclin D1 negative. In contrast, inhibition of cyclin-dependent kinase (CDK) 4/6 by PD0332991 caused cyclin D1-positive senescence in MEL10 cells. Both types of senescence were suppressed by rapamycin, converting it into reversible arrest. We confirmed that the inhibitor of CDK4/6 caused cyclin D1 positive senescence in normal RPE cells, whereas U0126 prevented cyclin D1 expression. Elimination of cyclin D1 by siRNA did not prevent other markers of senescence that are consistent with the lack of its effect on MTOR. Our data confirmed that a mere inhibition of the cell cycle was sufficient to cause senescence, providing MTOR was active, and inhibition of MEK partially inhibited MTOR in a cell-type-dependent manner. Second, hallmarks of senescence may be dissociated, and hyperelevated cyclin D1, a marker of hyperactivation of senescent cells, did not necessarily determine other markers of senescence. Third, inhibition of MEK was sufficient to eliminate cyclin D1, regardless of MTOR. In proliferating cells, MTOR (mechanistic Target of Rapamycin) stimulates cellular mass growth, whereas cyclins D and E initiate S-phase transition.1-4 Withdrawal of growth factors causes reversible cell-cycle arrest (quiescence) with low levels of cyclins and MTOR activity, reversible by re-addition of growth factors. In contrast, cell-cycle arrest in the presence of growth stimuli, which activate MTOR, leads to cellular senescence. 5,6 In other words, when the cell cycle is blocked, while growth-promoting pathways such as MTOR remain active, cells continue to grow in size and undergo senescence. A process of conversion from normal reversible arrest into senescence was named as gerogenic conversion (geroconversion).7 Cellular senescence is characterized by large flat morphology (hypertrophy), beta-Gal staining, very high levels of cyclins D1 and E, senescence-associated secretory phenotype and loss of replicative/regenerative potential (RP).7-12 Loss of RP means that cells cannot proliferate even when cell-cycle block is removed and cells re-enter the cell cycle.13,14 Rapamycin decreases hypertrophy and loss of RP, in a dose-dependent manner proportional to S6 dephosphorylation (a marker of MTORC1 activity). 15Other ...

show abstract

“…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.…”

Section: Perspectivesmentioning

confidence: 87%