Notch signaling maintains proliferation and survival of the HL60 human promyelocytic leukemia cell line and promotes the phosphorylation of the Rb protein.
The Notch signaling pathway has been implicated in the development of several leukemia and lymphoma. In order to investigate the relationship between Notch signaling and acute myeloid leukemia (AML), in this study, we expressed a recombinant Notch ligand protein, the DSL domain of the human Jagged1 fused with GST (GST-Jag1). GST-Jag1 could activate Notch signaling in the human promyelocytic leukemia cell line HL60, as shown by a reporter assay and the induced expression of Notch effector gene Hes1 and Hes5. However, GST-Jag1 had no effect on the proliferation and survival of HL60 cells. HL60 cells expressed both Notch ligands and receptors, and had a potential of reciprocal stimulation of Notch signaling between cells. We, therefore, blocked Notch signaling in cultured HL60 cells using a gamma-secretase inhibitor (GSI). We found that GSI inhibited the proliferation of HL60 cells significantly by blocking the cell-cycle progression in the G1 phase. Furthermore, GSI induced remarkably apoptosis of HL60 cells. These changes in GSI-treated HL60 cells correlated with the down-regulation of c-Myc and Bcl2, and the low phosphorylation of the Rb protein. These results suggested that reciprocal Notch signaling might be necessary for the proliferation and survival of AML cells, possibly through the maintenance of the expression of c-Myc and Bcl2, as well as the phosphorylation of the Rb protein.
Li
Guo-Hui
GH
Department of Hematology, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
Fan
Yu-Zhen
YZ
Liu
Xiao-Wei
XW
Zhang
Bing-Fang
BF
Yin
Dan-Dan
DD
He
Fei
F
Huang
Si-Yong
SY
Kang
Zhi-Jie
ZJ
Xu
Heng
H
Liu
Qiang
Q
Wu
Yan-Lan
YL
Niu
Xiao-Li
XL
Zhang
Li
L
Liu
Li
L
Hao
Miao-Wang
MW
Han
Hua
H
Liang
Ying-Min
YM
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D000072056:Transcription Factor HES-1; D014162:Transfection
D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D000072099:Serrate-Jagged Proteins; D000072056:Transcription Factor HES-1; C000606273:JAG1 protein, human; C489427:MYC protein, human; C077478:HES5 protein, human; C078493:HES1 protein, human