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PMID: 11134523 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 98 ·No. 1 ·2001-01-02 ·Pages 136-41

Aoki M, Blazek E, Vogt PK

Abstract

The oncoproteins P3k (homolog of the catalytic subunit of class IA phosphoinositide 3-kinase) and Akt (protein kinase B) induce oncogenic transformation of chicken embryo fibroblasts. The transformed cells show constitutive phosphorylation of the positive regulator of translation p70S6 kinase (S6K) and of the eukaryotic initiation factor 4E-BP1 binding protein (4E-BP1), a negative regulator of translation. Phosphorylation activates S6K and inactivates 4E-BP1. A mutant of Akt that retains kinase activity but does not induce phosphorylation of S6K or of 4E-BP1 fails to transform chicken embryo fibroblasts, suggesting a correlation between the oncogenicity of Akt and phosphorylation of S6K and 4E-BP1. The macrolide antibiotic rapamycin effectively blocks oncogenic transformation induced by either P3k or Akt but does not reduce the transforming activity of 11 other oncoproteins. Rapamycin inhibits the kinase mTOR, an important regulator of translation, and this inhibition requires binding of the antibiotic to the immunophilin FKBP12. Displacement of rapamycin from FKBP12 relieves the inhibition of mTOR and also restores P3k-induced transformation. These data are in accord with the hypothesis that transformation by P3k or Akt involves intervention in translational controls.

MeSH Terms
Animals Carrier Proteins Cell Transformation, Neoplastic/drug effects Cells, Cultured Chick Embryo Enzyme Activation Fibroblasts Mutation Oncogene Proteins/antagonists & inhibitors,metabolism Phosphatidylinositol 3-Kinases/metabolism Phosphoinositide-3 Kinase Inhibitors Phosphoproteins/analysis,metabolism Phosphorylation/drug effects Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors,metabolism Platelet-Derived Growth Factor/pharmacology Protein Biosynthesis Protein Kinases Protein Serine-Threonine Kinases Proto-Oncogene Proteins/antagonists & inhibitors,metabolism Proto-Oncogene Proteins c-akt Ribosomal Protein S6 Kinases/metabolism Sirolimus/pharmacology TOR Serine-Threonine Kinases Tacrolimus Binding Protein 1A/metabolism
Chemicals
Carrier Proteins Oncogene Proteins Phosphoinositide-3 Kinase Inhibitors Phosphoproteins Platelet-Derived Growth Factor Proto-Oncogene Proteins Protein Kinases Phosphotransferases (Alcohol Group Acceptor) Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Ribosomal Protein S6 Kinases TOR Serine-Threonine Kinases Tacrolimus Binding Protein 1A Sirolimus
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Aoki M
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Blazek E
Vogt P K
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.011528498
Published
2001-01-02
Pages
136-41
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC14557
Subset
IM
Grants
NCI NIH HHS · R01 CA079616 · United States
NCI NIH HHS · R01 CA078230 · United States
NCI NIH HHS · CA78230 · United States
NCI NIH HHS · CA79616 · United States
NCI NIH HHS · CA42564 · United States
External Links
PubMed source DOI: 10.1073/pnas.011528498 PMC Full Text View journal details
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