Notch-1 inhibits apoptosis in murine erythroleukemia cells and is necessary for differentiation induced by hybrid polar compounds.
Strikingly increased expression of notch-1 has been demonstrated in several human malignancies and pre-neoplastic lesions. However, the functional consequences of notch-1 overexpression in transformed cells remain unclear. We investigated whether endogenously expressed notch-1 controls cell fate determination in mouse erythroleukemia (MEL) cells during pharmacologically induced differentiation. We found that notch-1 expression is modulated during MEL cell differentiation. Premature downregulation of notch-1 during differentiation, by antisense S-oligonucleotides or by enforced expression of antisense notch-1 mRNA, causes MEL cells to abort the differentiation program and undergo apoptosis. Downregulation of notch-1 expression in the absence of differentiation inducer increases the likelihood of spontaneous apoptosis. We conclude that in MEL cells, endogenous notch-1 expression controls the apoptotic threshold during differentiation and growth. In these cells, notch-1 allows differentiation by preventing apoptosis of pre-committed cells. This novel function of notch-1 may play a role in regulating apoptosis susceptibility in notch-1 expressing tumor cells.
Shelly
L L
LL
Laboratory of Cell Biology, Center For Biologics Evaluation and Research, Food and Drug Administration, National Institutes of Health, Bethesda, Maryland 20892, USA.
Fuchs
C
C
Miele
L
L
D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division; D002999:Clone Cells; D015536:Down-Regulation; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D000081:Acetamides; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; C014026:hexamethylene bisacetamide