期刊
GENES CHROMOSOMES & CANCER
卷 54, 期 8, 页码 516-526出版社
WILEY
DOI: 10.1002/gcc.22264
关键词
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资金
- MIUR [PRIN 2008-2008ZFYEY3_003]
- Transition Grant, Universita degli Studi di Milano
- Associazione Italiana Ricerca sul Cancro [IG 10136]
- Fondazione Umberto Veronesi
- Dept. of Health Science, Universita degli Studi di Milano
- PhD program of the Doctorate School in Molecular and Translational Medicine, Universita degli Studi di Milano
The pathways of NOTCH and PI3K/AKT are dysregulated in about 60% and 48% of T-cell acute lymphoblastic leukemia (T-ALL) patients, respectively. In this context, they interact and cooperate in controlling tumor cell biology. Here, we propose a novel mechanism by which the PI3K/AKT pathway regulates NOTCH1 in T-ALL, starting from the evidence that the inhibition of PI3K/AKT signaling induced by treatment with LY294002 or transient transfection with a dominant negative AKT mutant downregulates NOTCH1 protein levels and activity, without affecting NOTCH1 transcription. We showed that the withdrawal of PI3K/AKT signaling was associated to NOTCH1 phosphorylation in tyrosine residues and monoubiquitination of NOTCH1 detected by Ubiquitin capture assay. Co-immunoprecipitation assay and colocalization analysis further showed that the E3 ubiquitin ligase c-Cbl interacts and monoubiquitinates NOTCH1, activating its lysosomal degradation. These results suggest that the degradation of NOTCH1 could represent a mechanism of control by which NOTCH1 receptors are actively removed from the cell surface. This mechanism is finely regulated by the PI3K/AKT pathway in physiological conditions. In pathological conditions characterized by PI3K/AKT hyperactivation, such as T-ALL, the excessive AKT signaling could lead to NOTCH1 signaling dysregulation. Therefore, a therapeutic strategy directed to PI3K/AKT in T-ALL could contemporaneously inhibit the dysregulated NOTCH1 signaling. (c) 2015 Wiley Periodicals, Inc.
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