The mTOR inhibitor rapamycin down-regulates the expression of the ubiquitin ligase subunit Skp2 in breast cancer cells

Shapira, Maanit; Kakiashvili, Eli; Rosenberg, Tzur; Hershko, Dan

doi:10.1186/bcr1533

Cited by 65 publications

(56 citation statements)

References 30 publications

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“…In addition, RAD001 might control the protein levels of p27Kip1 by down-regulating its specific ubiquitin ligase subunit, Skp2 (24). We found both cyclin D1 and cyclin D3 proteins up-regulated in mutant thyroids compared with wild-type controls, whereas p27Kip1 levels were not altered by Pten loss (Fig.…”

Section: Resultsmentioning

confidence: 55%

Mammalian Target of Rapamycin Is the Key Effector of Phosphatidylinositol-3-OH–Initiated Proliferative Signals in the Thyroid Follicular Epithelium

Yeager¹,

Brewer²,

Cai

et al. 2008

Cancer Research

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Activation of the phosphatidylinositol-3-OH kinase (PI3K) signaling cascade is becoming increasingly recognized as a common feature of thyroid follicular neoplasms. We have recently shown that conditional loss of Pten in the mouse thyroid follicular cells is sufficient to stimulate continuous autonomous growth, leading to a homogeneously hyperplastic gland and to the development of follicular adenomas. Because the PI3K/AKT cascade can activate a plethora of different signaling pathways, it is still unclear which of these may represent the key mitogenic output of PI3K-initiated signaling. Here, we show that the in vivo proliferative response to chronic PI3K activation profoundly relies on the activation of the mammalian target of rapamycin (mTOR)/S6K1 axis, and that mTOR inhibition in Pten mutant mice and cells restores virtually normal proliferation rates, despite the presence of still elevated Akt activity, at least in part by down-regulating cyclins D1 and D3, and without affecting cell survival. [Cancer Res 2008;68(2):444-9]

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Section: Resultsmentioning

confidence: 55%

Mammalian Target of Rapamycin Is the Key Effector of Phosphatidylinositol-3-OH–Initiated Proliferative Signals in the Thyroid Follicular Epithelium

Yeager¹,

Brewer²,

Cai

et al. 2008

Cancer Research

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“…Inhibition of mTORC1 has been shown to stabilise p27 mRNA and to promote cap-independent translation of p27 mRNA, hence both mRNA and protein levels may be upregulated independent of gene activation [31]. A recent study in human breast-cancer cell lines has shown that inhibition of mTORC1 with rapamycin also leads to reduced p27 protein degradation via decreased expression of the ubiquitin ligase subunit Skp2 [41]. Hence the early increase in p27 protein levels may also be due to a decrease in p27 degradation.…”

Section: Resultsmentioning

confidence: 99%

Early loss of mammalian target of rapamycin complex 1 (mTORC1) signalling and reduction in cell size during dominant-negative suppression of hepatic nuclear factor 1-α (HNF1A) function in INS-1 insulinoma cells

et al. 2008

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Aims/hypothesis Mutations in the HNF1A (previously known as TCF1) gene encoding hepatocyte nuclear factor-1α (HNF1A) lead to the development of maturity-onset diabetes of the young, type 3 (HNF1A-MODY), characterised by impaired insulin secretion and a reduction in beta cell mass. HNF1A plays an important role in pancreatic beta cell differentiation and survival. The mammalian target of rapamycin (mTOR) is a central growth factor-and nutrientactivated protein kinase controlling cell metabolism, growth and survival. We investigated the role of mTOR inactivation in the decline in beta cell mass in a cellular model of HNF1A-MODY. Methods Previously we showed that suppression of HNF1A function via expression of a dominant-negative mutant (DN-HNF1A) decreases insulin gene transcription in insulinoma (INS-1) cells. We investigated the signalling of two distinct mTOR protein complexes, mTORC1 and mTORC2, in response to DN-HNF1A induction.Results We observed delayed inactivation of mTORC2 48 h after DN-HNF1A induction, evidenced by a reduction in serine 473 phosphorylation of thymoma viral protooncogene 1 (AKT1). We also observed an early inactivation of mTORC1 24 h after DN-HNF1A induction, which was detected by decreases in threonine 389 phosphorylation of p70 ribosomal protein S6 kinase (S6K1) and serine 65 phosphorylation of translational inhibitor eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1). Flow cytometry and gene expression analysis demonstrated a preapoptotic decrease in INS-1 cell size in response to DN-HNF1A induction, and an increase in the level of the mTORC1-regulated cell-cycle inhibitor, cyclin-dependent kinase inhibitor 1B p27. Conclusions/interpretation Our data suggest that mTOR kinase and signalling through mTORC1 are highly sensitive to suppression of HNF1A function, and may contribute to disturbance of cell-size regulation and cell-cycle progression in HNF1A-MODY.

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“…43,44 Recently, it was shown that mouse embryonic fibroblasts deficient in the transcription factor Oct1 were insensitive to mTOR inhibition by rapamycin. 45 Oct1 was found to control transcription of p27 Kip1 in wild-type cells downstream of the mTOR pathway such that Oct1 negative cells failed to upregulate p27 Kip1 in response to rapamycin.…”

Section: A Comparative Analysis Of Rapamycin Effect On Rat Liver Cellmentioning

confidence: 99%

The physiology and pathophysiology of rapamycin resistance

Gruppuso

Boylan²,

Sanders³

2011

Cell Cycle

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The mTOR inhibitor rapamycin down-regulates the expression of the ubiquitin ligase subunit Skp2 in breast cancer cells

Cited by 65 publications

References 30 publications

Mammalian Target of Rapamycin Is the Key Effector of Phosphatidylinositol-3-OH–Initiated Proliferative Signals in the Thyroid Follicular Epithelium

Mammalian Target of Rapamycin Is the Key Effector of Phosphatidylinositol-3-OH–Initiated Proliferative Signals in the Thyroid Follicular Epithelium

Early loss of mammalian target of rapamycin complex 1 (mTORC1) signalling and reduction in cell size during dominant-negative suppression of hepatic nuclear factor 1-α (HNF1A) function in INS-1 insulinoma cells

The physiology and pathophysiology of rapamycin resistance

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