Reversal of tumorigenicity and the block to differentiation in erythroleukemia cells by GATA-1.
Oncogenic transformation usually inhibits normal cell differentiation processes. Certain chemical agents can force some tumor cells to resume their differentiation program and undergo cell cycle arrest, an approach termed differentiation therapy. Mouse erythroleukemia (MEL) cells represent an important cell culture model system for investigating the principles of differentiation therapy. MEL cells are malignant erythroblasts that are blocked from differentiating into mature erythroid cells because of inappropriate expression of the transcription factor PU.1, which binds to and represses GATA-1, a key transcriptional stimulator of red blood cell differentiation. We report here that the block to differentiation in MEL cells can be overcome by providing the cells with additional GATA-1. A conditionally active form of GATA-1 can trigger the cells to differentiate, undergo terminal cell division, and lose their tumorigenicity. We also show that the gene for the cell cycle inhibitor p21 is transcriptionally regulated by GATA-1 and is a likely downstream effector of GATA-1 that helps to promote differentiation and proliferation arrest.
Choe
Kevin S
KS
Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Radparvar
Farshid
F
Matushansky
Igor
I
Rekhtman
Natasha
N
Han
Xing
X
Skoultchi
Arthur I
AI
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015536:Down-Regulation; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; D015316:Genetic Therapy; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D011960:Receptors, Estrogen; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors