E2F-6 suppresses growth-associated apoptosis of human hematopoietic progenitor cells by counteracting proapoptotic activity of E2F-1.
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.
Kikuchi
Jiro
J
Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical School, 3311-1 Yakushiji, Shimotsuke-City, Tochigi 329-0498, Japan.
Shimizu
Rumi
R
Wada
Taeko
T
Ando
Hidenobu
H
Nakamura
Mitsuru
M
Ozawa
Keiya
K
Furukawa
Yusuke
Y
D017209:Apoptosis / Q000187:drug effects*; D053477:Apoptotic Protease-Activating Factor 1 / Q000096:biosynthesis / Q000235:genetics; D001667:Binding, Competitive; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D003114:Colony-Forming Units Assay; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology; D050684:E2F Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology; D050701:E2F6 Transcription Factor / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells / Q000166:cytology / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014161:Transduction, Genetic; D015854:Up-Regulation
C506592:APAF1 protein, human; D053477:Apoptotic Protease-Activating Factor 1; D016895:Culture Media, Serum-Free; D016207:Cytokines; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D050701:E2F6 Transcription Factor; C491744:E2F6 protein, human; D011993:Recombinant Fusion Proteins