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1 Department of Molecular Pharmacology, Stanford University, Stanford, CA, USA
2 Section of Endocrinology and Department of Molecular & Cellular Biology, VA Medical Center and Arizona State University, Tempe, AZ, USA
* To whom correspondence should be addressed. E-mail: rroth{at}stanford.edu.
Expression of constitutively active Akt3 was found to increase the size of MCF-7 cells approximately two-fold both in vitro as well as in vivo. A regulatable version of Akt1 (MER-Akt) was also found capable of inducing a two-fold increase in the size of H4IIE rat hepatoma cells. Rapamycin, a specific inhibitor of mTOR function, was found to inhibit the Akt induced increase in cell size by 70%, presumably via inhibition of the Akt-induced increase in protein synthesis. In order to determine whether Akt could be inhibiting protein degradation and thereby contributing to its ability to induce an increase in cell size, we conducted protein degradation experiments in the H4IIE cell line. Activation of the regulatable Akt was found to inhibit protein degradation to a comparable degree as insulin treatment. The effects of these two agents on protein degradation were not additive, thereby suggesting that they were acting on a similar pathway. An inhibitor of the phosphatidylinositol 3-kinase pathway, LY294002, blocked both the insulin and Akt induced inhibition of protein degradation, again consistent with the hypothesis that both of these agents were acting on the same pathway. In contrast, rapamycin, did not block the ability of either of these agents to inhibit protein degradation. These results indicate that Akt increases cell size through both mTOR-dependent and mTOR independent pathways and that the latter involves inhibition of protein degradation. These studies also are consistent with the hypothesis that insulin's ability to regulate protein degradation are to a large extent mediated via Akt.
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