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The mTOR pathway controls cell proliferation by regulating the FoxO3a transcription factor via SGK1 kinase.

Mori S, Nada S, Kimura H, Tajima S, Takahashi Y, Kitamura A, Oneyama C, Okada M - PLoS ONE (2014)

Bottom Line: Although Akt was activated by mTORC1 inactivation, FoxO3a was upregulated via an epigenetic mechanism and hypophosphorylated at Ser314, which resulted in its nuclear accumulation.Consistently, mTORC1 inactivation induced downregulation of serum- and glucocorticoid-inducible kinase 1 (SGK1), the kinase responsible for Ser314 phosphorylation.SGK1 overexpression suppressed CDKI expression in p18-deficient cells, whereas SGK1 knockdown induced CDKI expression in wild-type cells, resulting in the suppression of cell proliferation.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, Japan.

ABSTRACT
The mechanistic target of rapamycin (mTOR) functions as a component of two large complexes, mTORC1 and mTORC2, which play crucial roles in regulating cell growth and homeostasis. However, the molecular mechanisms by which mTOR controls cell proliferation remain elusive. Here we show that the FoxO3a transcription factor is coordinately regulated by mTORC1 and mTORC2, and plays a crucial role in controlling cell proliferation. To dissect mTOR signaling, mTORC1 was specifically inactivated by depleting p18, an essential anchor of mTORC1 on lysosomes. mTORC1 inactivation caused a marked retardation of cell proliferation, which was associated with upregulation of cyclin-dependent kinase inhibitors (CDKIs). Although Akt was activated by mTORC1 inactivation, FoxO3a was upregulated via an epigenetic mechanism and hypophosphorylated at Ser314, which resulted in its nuclear accumulation. Consistently, mTORC1 inactivation induced downregulation of serum- and glucocorticoid-inducible kinase 1 (SGK1), the kinase responsible for Ser314 phosphorylation. Expression of FoxO3a mutated at Ser314 suppressed cell proliferation by inducing CDKI expression. SGK1 overexpression suppressed CDKI expression in p18-deficient cells, whereas SGK1 knockdown induced CDKI expression in wild-type cells, resulting in the suppression of cell proliferation. These results suggest that mTORC1, in coordination with mTORC2, controls cell proliferation by regulating FoxO3a gene expression and SGK1-mediated phosphorylation of FoxO3a at Ser314.

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Schematic model of the function of mTOR pathway in the regulation of cell proliferation.(A) When mTORC1 is active. (B) When mTORC1 is inactive.
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pone-0088891-g008: Schematic model of the function of mTOR pathway in the regulation of cell proliferation.(A) When mTORC1 is active. (B) When mTORC1 is inactive.

Mentions: To dissect the function of mTOR in the regulation of cell proliferation, we investigated the effects of specific inactivation of mTORC1 using p18-deficient cells. Based on our findings, together with those of previous studies, we propose a hypothetical model for mTORC1 function (Figure 8). In WT cells, active mTORC1 promotes protein synthesis to support cell growth, and maintains the activity of Akt at a resting level through negative-feedback regulation via Grb10 [17]. Akt and SGK1 activated by mTORC2 [39] coordinately phosphorylate FoxO3a at Thr32/Ser253 and Ser314, respectively [34]. These modifications result in translocation of FoxO3a from the nucleus, thereby inhibiting expression of CDKIs and ultimately promoting cell proliferation. According to this model, mTORC2 must be constitutively active at an appropriate level to continuously promote cell proliferation. By contrast, when mTORC1 is inactivated, mTORC2 is activated by the induction of Rictor, potentially through the loss of negative-feedback inhibition of the mTORC1 pathway [40]. mTORC2 then induces Akt hyperactivation, resulting in elevated phosphorylation of FoxO3a at Thr32 and Ser253. The induction of Rictor also facilitates ubiquitylation-meditated destruction of SGK1 [36]. Consequently, phosphorylation of FoxO3a at Ser314 is reduced, and FoxO3a retained in the nucleus activates expression of CDKIs, thereby inducing growth arrest. In addition, mTORC1 inactivation alleviates the epigenetic suppression of Foxo3 gene expression, further enhancing the accumulation of FoxO3a in the nucleus. This model highlights the crucial role of the coordinated action of mTORC1 and mTORC2 in the regulation of cell proliferation via FoxO3a. When mTORC1 is inactivated under physiological conditions, such as starvation, activation of FoxO3a contributes to growth arrest; this process is critical for the survival of cells that are undergoing autophagy to recycle materials and obtain energy. Because we observed that expression and phosphorylation status of FoxO1 were significantly affected by mTORC1 inactivation, it is possible that other FoxO family members also contribute to the growth control via the mTOR pathway.


The mTOR pathway controls cell proliferation by regulating the FoxO3a transcription factor via SGK1 kinase.

Mori S, Nada S, Kimura H, Tajima S, Takahashi Y, Kitamura A, Oneyama C, Okada M - PLoS ONE (2014)

Schematic model of the function of mTOR pathway in the regulation of cell proliferation.(A) When mTORC1 is active. (B) When mTORC1 is inactive.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928304&req=5

pone-0088891-g008: Schematic model of the function of mTOR pathway in the regulation of cell proliferation.(A) When mTORC1 is active. (B) When mTORC1 is inactive.
Mentions: To dissect the function of mTOR in the regulation of cell proliferation, we investigated the effects of specific inactivation of mTORC1 using p18-deficient cells. Based on our findings, together with those of previous studies, we propose a hypothetical model for mTORC1 function (Figure 8). In WT cells, active mTORC1 promotes protein synthesis to support cell growth, and maintains the activity of Akt at a resting level through negative-feedback regulation via Grb10 [17]. Akt and SGK1 activated by mTORC2 [39] coordinately phosphorylate FoxO3a at Thr32/Ser253 and Ser314, respectively [34]. These modifications result in translocation of FoxO3a from the nucleus, thereby inhibiting expression of CDKIs and ultimately promoting cell proliferation. According to this model, mTORC2 must be constitutively active at an appropriate level to continuously promote cell proliferation. By contrast, when mTORC1 is inactivated, mTORC2 is activated by the induction of Rictor, potentially through the loss of negative-feedback inhibition of the mTORC1 pathway [40]. mTORC2 then induces Akt hyperactivation, resulting in elevated phosphorylation of FoxO3a at Thr32 and Ser253. The induction of Rictor also facilitates ubiquitylation-meditated destruction of SGK1 [36]. Consequently, phosphorylation of FoxO3a at Ser314 is reduced, and FoxO3a retained in the nucleus activates expression of CDKIs, thereby inducing growth arrest. In addition, mTORC1 inactivation alleviates the epigenetic suppression of Foxo3 gene expression, further enhancing the accumulation of FoxO3a in the nucleus. This model highlights the crucial role of the coordinated action of mTORC1 and mTORC2 in the regulation of cell proliferation via FoxO3a. When mTORC1 is inactivated under physiological conditions, such as starvation, activation of FoxO3a contributes to growth arrest; this process is critical for the survival of cells that are undergoing autophagy to recycle materials and obtain energy. Because we observed that expression and phosphorylation status of FoxO1 were significantly affected by mTORC1 inactivation, it is possible that other FoxO family members also contribute to the growth control via the mTOR pathway.

Bottom Line: Although Akt was activated by mTORC1 inactivation, FoxO3a was upregulated via an epigenetic mechanism and hypophosphorylated at Ser314, which resulted in its nuclear accumulation.Consistently, mTORC1 inactivation induced downregulation of serum- and glucocorticoid-inducible kinase 1 (SGK1), the kinase responsible for Ser314 phosphorylation.SGK1 overexpression suppressed CDKI expression in p18-deficient cells, whereas SGK1 knockdown induced CDKI expression in wild-type cells, resulting in the suppression of cell proliferation.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, Japan.

ABSTRACT
The mechanistic target of rapamycin (mTOR) functions as a component of two large complexes, mTORC1 and mTORC2, which play crucial roles in regulating cell growth and homeostasis. However, the molecular mechanisms by which mTOR controls cell proliferation remain elusive. Here we show that the FoxO3a transcription factor is coordinately regulated by mTORC1 and mTORC2, and plays a crucial role in controlling cell proliferation. To dissect mTOR signaling, mTORC1 was specifically inactivated by depleting p18, an essential anchor of mTORC1 on lysosomes. mTORC1 inactivation caused a marked retardation of cell proliferation, which was associated with upregulation of cyclin-dependent kinase inhibitors (CDKIs). Although Akt was activated by mTORC1 inactivation, FoxO3a was upregulated via an epigenetic mechanism and hypophosphorylated at Ser314, which resulted in its nuclear accumulation. Consistently, mTORC1 inactivation induced downregulation of serum- and glucocorticoid-inducible kinase 1 (SGK1), the kinase responsible for Ser314 phosphorylation. Expression of FoxO3a mutated at Ser314 suppressed cell proliferation by inducing CDKI expression. SGK1 overexpression suppressed CDKI expression in p18-deficient cells, whereas SGK1 knockdown induced CDKI expression in wild-type cells, resulting in the suppression of cell proliferation. These results suggest that mTORC1, in coordination with mTORC2, controls cell proliferation by regulating FoxO3a gene expression and SGK1-mediated phosphorylation of FoxO3a at Ser314.

Show MeSH
Related in: MedlinePlus