title: Notch-1 regulates Akt signaling pathway and the expression of cell cycle regulatory proteins cyclin D1, CDK2 and p21 in T-ALL cell lines.
abstract: Gain-of-function mutations in Notch-1 are common in T-cell lymphoblastic leukemia (T-ALL), making this receptor a promising target for drugs such as gamma-secretase inhibitors (GSIs). However, GSIs seem to be active in only a small fraction of T-ALL cell lines with constitutive Notch-1 activity and the downstream response of Notch signaling is only partially understood. To further investigate the molecular mechanisms underlying proliferation suppression and apoptosis and explore effective downstream target genes, we used RNA interference (RNAi) technology to down-regulate the expression of Notch-1 in GSIs-resistant T-ALL cell lines. Results showed that down-regulation of Notch-1 by transfection of a small interfering RNA (siRNA) could cause SupT1 cells proliferation inhibition by inducing G(0)/G(1) cell cycle arrest and apoptosis. The proliferation inhibitory and apoptotic effects resulting from down-regulation of Notch-1 may be mediated through regulating the expression of cell cycle regulatory proteins cyclin D1, CDK2 and p21 and the activity of Akt signaling. In addition, our results demonstrated that down-regulation of Notch-1 signaling could sensitize SupT1 cells to adriamycin. Taken together, cell cycle regulatory proteins and Akt signaling may be attractive targets in T-ALL.
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong 250012, PR China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Guo
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ye
authors.forename: Jianjian
authors.initials: J
authors.lastname: Dai
authors.forename: Lizhen
authors.initials: L
authors.lastname: Li
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Daoxin
authors.initials: D
authors.lastname: Ma
authors.forename: Chunyan
authors.initials: C
authors.lastname: Ji
mesh_terms: D017209:Apoptosis; D001483:Base Sequence; D016203:CDC2 Protein Kinase / Q000235:genetics*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D015536:Down-Regulation / Q000502:physiology; D006801:Humans; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D051881:Receptor, Notch1 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C497761:NOTCH1 protein, human; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; D016203:CDC2 Protein Kinase