Gene interactions and pathways from curated databases and text-mining
Blood 2008, PMID: 18339899

Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma.

Dal Col, Jessica; Zancai, Paola; Terrin, Liliana; Guidoboni, Massimo; Ponzoni, Maurilio; Pavan, Alessandro; Spina, Michele; Bergamin, Stefano; Rizzo, Silvana; Tirelli, Umberto; De Rossi, Anita; Doglioni, Claudio; Dolcetti, Riccardo

Functional characterization of signaling pathways that critically control mantle cell lymphoma (MCL) cell growth and survival is relevant to designing new therapies for this lymphoma. We herein demonstrate that the constitutive activation of Akt correlates with the expression of the phosphorylated, inactive form of PTEN. Phosphatidyl-inositol-3 kinase (PI3-K)/Akt or mammalian target of rapamycin (mTOR) inhibition decreased the growth of both primary MCL cultures and established cell lines and antagonizes the growth-promoting activity of CD40 triggering and IL-4. These effects are mediated by nuclear accumulation of the p27(Kip1) inhibitor induced by down-regulation of the p45(Skp2) and Cks1 proteins, which target p27(Kip1) for degradation. Moreover, Akt inhibition down-regulated cyclin D1 by promoting its proteasome-dependent degradation driven by GSK-3. Intriguingly, mTOR inhibition affected cyclin D1 proteolysis only in MCL cells in which GSK-3 is under the direct control of mTOR, suggesting that different MCL subsets could be differently responsive to mTOR inhibition. Finally, PI3-K/Akt inhibitors, but not rapamycin, induced variable levels of caspase-dependent apoptosis and reduced telomerase activity. These results indicate that Akt and mTOR activation have distinct functional relevance in MCL and suggest that targeting Akt may result in more effective therapeutic effects compared with mTOR inhibition.

Diseases/Pathways annotated by Medline MESH: Lymphoma, Mantle-Cell
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Text Mining Data

p27 → p45: " These effects are mediated by nuclear accumulation of the p27 ( Kip1 ) inhibitor induced by down-regulation of the p45 ( Skp2 ) and Cks1 proteins, which target p27 ( Kip1 ) for degradation "

cyclin D1 → Akt: " Moreover, Akt inhibition down-regulated cyclin D1 by promoting its proteasome dependent degradation driven by GSK-3 "

cyclin D1 — mTOR: " Intriguingly, mTOR inhibition affected cyclin D1 proteolysis only in MCL cells in which GSK-3 is under the direct control of mTOR, suggesting that different MCL subsets could be differently responsive to mTOR inhibition "

Manually curated Databases

No curated data.