Suppression of erythroid but not megakaryocytic differentiation of human K562 erythroleukemic cells by notch-1.
The Notch signal transduction pathway is a highly conserved regulatory system that controls multiple developmental processes. We have established an erythroleukemia cell model to study how Notch regulates cell fate and erythroleukemic cell differentiation. K562 and HEL cells expressed the Notch-1 receptor and the Notch ligand Jagged-1. The stable expression of the constitutively active intracellular domain of Notch-1 (NIC-1) in K562 cells inhibited erythroid without affecting megakaryocytic maturation. Expression of antisense Notch-1 induced spontaneous erythroid maturation. Suppression of erythroid maturation by NIC-1 did not result from down-regulation of GATA-1 and TAL-1, transcription factors necessary for erythroid differentiation. Microarray gene expression analysis identified genes activated during erythroid maturation, and NIC-1 disrupted the maturation-dependent changes in the expression of these genes. These results show that NIC-1 alters the pattern of gene expression in K562 cells leading to a block in erythroid maturation and therefore suggest that Notch signaling may control the developmental potential of normal and malignant erythroid progenitor cells.
Lam
L T
LT
University of Wisconsin Medical School, Department of Pharmacology, Molecular and Cellular Pharmacology Program, Madison, Wisconsin 53706, USA.
Ronchini
C
C
Norton
J
J
Capobianco
A J
AJ
Bresnick
E H
EH
D051792:Basic Helix-Loop-Helix Proteins; D001560:Benzidines / Q000494:pharmacology; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation / Q000502:physiology; D016373:DNA, Antisense / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004912:Erythrocytes / Q000166:cytology*; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D006427:Hemin / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism; D008024:Ligands; D008533:Megakaryocytes / Q000166:cytology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D010957:Plasmids; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000378:metabolism; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D012190:Retroviridae / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
D051792:Basic Helix-Loop-Helix Proteins; D001560:Benzidines; D002135:Calcium-Binding Proteins; D016373:DNA, Antisense; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D006427:Hemin; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D000072099:Serrate-Jagged Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C494688:GATA1 protein, human; C000606273:JAG1 protein, human; C497761:NOTCH1 protein, human; C067143:TAL1 protein, human; C029876:benzidine