scholarly journals Myc Inhibits p27-Induced Erythroid Differentiation of Leukemia Cells by Repressing Erythroid Master Genes without Reversing p27-Mediated Cell Cycle Arrest

2008 ◽  
Vol 28 (24) ◽  
pp. 7286-7295 ◽  
Author(s):  
Juan C. Acosta ◽  
Nuria Ferrándiz ◽  
Gabriel Bretones ◽  
Verónica Torrano ◽  
Rosa Blanco ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
K562 Cells ◽  
Erythroid Differentiation ◽  
Erythroid Cell ◽  
Specific Gene ◽  
Human Leukemia ◽  
Cycle Arrest ◽  
Conditional Expression ◽  
Inhibition Of Differentiation

ABSTRACT Inhibition of differentiation has been proposed as an important mechanism for Myc-induced tumorigenesis, but the mechanisms involved are unclear. We have established a genetically defined differentiation model in human leukemia K562 cells by conditional expression of the cyclin-dependent kinase (Cdk) inhibitor p27 (inducible by Zn2+) and Myc (activatable by 4-hydroxy-tamoxifen). Induction of p27 resulted in erythroid differentiation, accompanied by Cdk inhibition and G1 arrest. Interestingly, activation of Myc inhibited p27-mediated erythroid differentiation without affecting p27-mediated proliferation arrest. Microarray-based gene expression indicated that, in the presence of p27, Myc blocked the upregulation of several erythroid-cell-specific genes, including NFE2, JUNB, and GATA1 (transcription factors with a pivotal role in erythropoiesis). Moreover, Myc also blocked the upregulation of Mad1, a transcriptional antagonist of Myc that is able to induce erythroid differentiation. Cotransfection experiments demonstrated that Myc-mediated inhibition of differentiation is partly dependent on the repression of Mad1 and GATA1. In conclusion, this model demonstrates that Myc-mediated inhibition of differentiation depends on the regulation of a specific gene program, whereas it is independent of p27-mediated cell cycle arrest. Our results support the hypothesis that differentiation inhibition is an important Myc tumorigenic mechanism that is independent of cell proliferation.

scholarly journals Correction: Wogonin induces cell cycle arrest and erythroid differentiation in imatinib-resistant K562 cells and primary CML cells

Oncotarget ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 300-301
Author(s):  
Hao Yang ◽  
Hui Hui ◽  
Qian Wang ◽  
Hui Li ◽  
Kai Zhao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
K562 Cells ◽  
Erythroid Differentiation ◽  
Cycle Arrest ◽  
Imatinib Resistant

Fog1 and Cebpa Are DNA Targets of GATA-1/PU.1 Antagonism during Leukemia Differentiation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4121-4121
Author(s):  
Pavel Burda ◽  
Nikola Curik ◽  
Juraj Kokavec ◽  
Vit Pospisil ◽  
Arthur I. Skoultchi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factors ◽  
Cell Cycle Arrest ◽  
Binding Sites ◽  
Erythroid Differentiation ◽  
Erythroid Cell ◽  
Differentiation Markers ◽  
Cycle Arrest ◽  
Mutual Antagonism ◽  
Murine Erythroleukemia

Abstract PU.1 and GATA1 are hematopoietic lineage-specific transcription factors that play key roles in normal myeloid and erythroid differentiation respectively. Inappropriate expression of PU.1 in proerythroblasts causes its binding to GATA-1 on DNA resulting in a block of erythroid differentiation and development of murine erythroleukemia (MEL) (Rekhtman 1999). Activation of a conditional transgene of GATA-1 (fused with the ligand binding domain of the estrogen receptor, ER) in MEL cells disrupts PU.1-mediated repression in chromatin leading to re-intiation of erythroid differentiation and cell cycle arrest (Choe 2003, Stopka 2005). In this study we show that MEL cells can also be induced to express myeloid differentiation programs upon PU.1-ER activation. Gene expression microarray analysis of GATA-1-ER MEL cells and PU.1-ER MEL cells treated with ER activators allowed us to identify mRNAs that are regulated by both GATA-1 and PU.1 including the set of GATA-1 targets repressed by PU.1, as well as the set of PU.1 targets repressed by GATA-1 in MEL cells. The targets of mutual antagonism of PU.1 and GATA-1 consisted of lineage specific transcription factors, differentiation markers and genes that cause cell cycle arrest and antiapoptotic regulators previously associated with myeloid and erythroid cell differentiation. To determine if PU.1 and GATA-1 directly regulate the lineage specific transcription factor genes, we performed chromatin immunoprecipitation (ChIP) and analyzed the ChIP samples on microarrays and by qPCR. We found that PU.1 and GATA-1 are localized near PU.1 binding sites in the genes for myeloid transcription factors Cebpa and Cbfb and near GATA-1 binding sites in the genes for erythroid transcription factors Fog1 and Nfe2. In addition, further ChIP experiments delineated chromatin architecture near the binding sites for PU.1 and GATA-1 including histone H3 content and acetylation of histone H3K9. We propose that the mutual antagonism of PU.1 and GATA-1 in inhibiting the respective differentiation programs is rendered through specific changes in chromatin structure around lineage specific transcription factors genes. These changes may contribute to the block to differentiation evident in leukemias.

scholarly journals Wogonin induces cell cycle arrest and erythroid differentiation in imatinib-resistant K562 cells and primary CML cells

Oncotarget ◽  
2014 ◽  
Vol 5 (18) ◽  
pp. 8188-8201 ◽  
Author(s):  
Hao Yang ◽  
Hui Hui ◽  
Qian Wang ◽  
Hui Li ◽  
Kai Zhao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
K562 Cells ◽  
Erythroid Differentiation ◽  
Cycle Arrest ◽  
Imatinib Resistant
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