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Constitutively active Rheb induces oncogenic transformation

Oncogene volume 27, pages 5729–5740 (2008)Cite this article

Abstract

Rheb (Ras-homolog enriched in brain) is a component of the phosphatidylinositol 3-kinase (PI3K) target of rapamycin (TOR) signaling pathway, functioning as a positive regulator of TOR. Constitutively active mutants of Rheb induce oncogenic transformation in cell culture. The transformed cells are larger and contain more protein than their normal counterparts. They show constitutive phosphorylation of the ribosomal protein S6 kinase and the eukaryotic initiation factor 4E-binding protein 1, two downstream targets of TOR. The TOR-specific inhibitor rapamycin strongly interferes with transformation induced by constitutively active Rheb, suggesting that TOR activity is essential for the oncogenic effects of mutant Rheb. Rheb-induced transformation is also dependent on a C-terminal farnesylation signal that mediates localization to a cellular membrane. An engineered N-terminal myristylation signal can substitute for the farnesylation. Immunofluorescence localizes wild-type and mutant Rheb to vesicular structures in the cytoplasm, overlapping with the endoplasmic reticulum.

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Abbreviations

4E-BP1:

eukaryotic initiation factor 4E-binding protein 1

Akt:

v-akt murine thymoma viral oncogene homolog

CEF:

chicken embryonic fibroblast

eIF4E:

eukaryotic initiation factor 4E

ER:

endoplasmic reticulum

FOXO-1:

forkhead box protein class-O 1

GAP:

GTPase-activating protein

PI3K:

phosphatidylinositol 3-kinase

PIP3:

phosphatidylinositol 3,4,5-trisphosphate

Ras:

rat sarcoma

Rheb:

Ras-homolog enriched in brain

S6K:

ribosomal protein S6 kinase

TOR:

target of rapamycin

TSC:

tuberous sclerosis complex

YB-1:

Y box-binding protein 1

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Acknowledgements

We thank Lynn Ueno, Dr Marco Gymnopoulos, Dr Peiging Sun and Dr William B Kiosses (Core Microscopy, The Scripps Research Institute) for expert technical assistance. This study was supported by grants from the National Cancer Institute. This article is numbered 19286 in the Scripps Research Institute.

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    H Jiang & P K Vogt

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Jiang, H., Vogt, P. Constitutively active Rheb induces oncogenic transformation. Oncogene 27, 5729–5740 (2008). https://doi.org/10.1038/onc.2008.180

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