RRC ID 53208
Author Kikuchi J, Shimizu R, Wada T, Ando H, Nakamura M, Ozawa K, Furukawa Y.
Title E2F-6 suppresses growth-associated apoptosis of human hematopoietic progenitor cells by counteracting proapoptotic activity of E2F-1.
Journal Stem Cells
Abstract E2F-6 is a dominant-negative transcriptional repressor against other members of the E2F family. In this study, we investigated the expression and function of E2F-6 in human hematopoietic progenitor cells to clarify its role in hematopoiesis. We found that among E2F subunits, E2F-1, E2F-2, E2F-4, and E2F-6 were expressed in CD34(+) human hematopoietic progenitor cells. The expression of E2F-6 increased along with proliferation and decreased during differentiation of hematopoietic progenitors, whereas the other three species were upregulated in CD34(-) bone marrow mononuclear cells. Overexpression of E2F-6 did not affect the growth of immature hematopoietic cell line K562 but suppressed E2F-1-induced apoptosis, whereas it failed to inhibit apoptosis induced by differentiation inducers and anticancer drugs. Among E2F-1-dependent apoptosis-related molecules, E2F-6 specifically inhibited upregulation of Apaf-1 by competing with E2F-1 for promoter binding. E2F-6 similarly suppressed apoptosis and Apaf-1 upregulation in primary hematopoietic progenitor cells during cytokine-induced proliferation but had no effect when they were differentiated. As a result, E2F-6 enhanced the clonogenic growth of colony-forming unit-granulocyte, erythroid, macrophage, and megakaryocyte. These results suggest that E2F-6 provides a failsafe mechanism against loss of hematopoietic progenitor cells during proliferation. Disclosure of potential conflicts of interest is found at the end of this article.
Volume 25(10)
Pages 2439-47
Published 2007-10-1
DOI 10.1634/stemcells.2007-0207
PII 2007-0207
PMID 17600109
MeSH Apoptosis / drug effects* Apoptotic Protease-Activating Factor 1 / biosynthesis Apoptotic Protease-Activating Factor 1 / genetics Binding, Competitive Cell Differentiation / drug effects Cells, Cultured / cytology Cells, Cultured / drug effects Colony-Forming Units Assay Culture Media, Serum-Free / pharmacology Cytokines / pharmacology E2F Transcription Factors / biosynthesis E2F Transcription Factors / genetics E2F1 Transcription Factor / antagonists & inhibitors E2F1 Transcription Factor / pharmacology E2F6 Transcription Factor / physiology* Hematopoietic Stem Cells / cytology Hematopoietic Stem Cells / drug effects* Humans K562 Cells / cytology K562 Cells / drug effects Promoter Regions, Genetic / drug effects Recombinant Fusion Proteins / physiology Transduction, Genetic Up-Regulation
IF 6.022
Times Cited 22
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