Gene interactions and pathways from curated databases and text-mining
Blood 2007, PMID: 17179228

Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML.

Zeng, Zhihong; Sarbassov, Dos D; Samudio, Ismael J; Yee, Karen W L; Munsell, Mark F; Ellen Jackson, C; Giles, Francis J; Sabatini, David M; Andreeff, Michael; Konopleva, Marina

The mTOR complex 2 (mTORC2) containing mTOR and rictor is thought to be rapamycin insensitive and was recently shown to regulate the prosurvival kinase AKT by phosphorylation on Ser473. We investigated the molecular effects of mTOR inhibition by the rapamycin derivatives (RDs) temsirolimus (CCI-779) and everolimus (RAD001) in acute myeloid leukemia (AML) cells. Unexpectedly, RDs not only inhibited the mTOR complex 1 (mTORC1) containing mTOR and raptor with decreased p70S6K, 4EPB1 phosphorylation, and GLUT1 mRNA, but also blocked AKT activation via inhibition of mTORC2 formation. This resulted in suppression of phosphorylation of the direct AKT substrate FKHR and decreased transcription of D-cyclins in AML cells. Similar observations were made in samples from patients with hematologic malignancies who received RDs in clinical studies. Our study provides the first evidence that rapamycin derivatives inhibit AKT signaling in primary AML cells both in vitro and in vivo, and supports the therapeutic potential of mTOR inhibition strategies in leukemias.

Diseases/Pathways annotated by Medline MESH: Leukemia, Myeloid, Acute
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Text Mining Data

mTORC2 ⊣ AKT: " Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML "

AKT ⊣ RDs: " Unexpectedly, RDs not only inhibited the mTOR complex 1 (mTORC1) containing mTOR and raptor with decreased p70S6K, 4EPB1 phosphorylation, and GLUT1 mRNA, but also blocked AKT activation via inhibition of mTORC2 formation "

mTOR complex 1 (mTORC1) ⊣ RDs: " Unexpectedly, RDs not only inhibited the mTOR complex 1 (mTORC1) containing mTOR and raptor with decreased p70S6K, 4EPB1 phosphorylation, and GLUT1 mRNA, but also blocked AKT activation via inhibition of mTORC2 formation "

Manually curated Databases

No curated data.