Submitted on March 27, 2007
Accepted on June 18, 2007
TISSUE-SPECIFIC STEM CELLS
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E2F-6 Suppresses Growth-associated Apoptosis of Human Hematopoietic Progenitor Cells by Counteracting Proapoptotic Activity of E2F-1
Jiro Kikuchi 1,
Rumi Shimizu 1,
Taeko Wada 1,
Hidenobu Ando 2,
Mitsuru Nakamura 2,
Keiya Ozawa 3,
Yusuke Furukawa 4*
1 Division of Stem Cell Regulation, Center for Molecular Medicine, Shimotsuke, Tochigi, Japan
2 Cell Regulation Analysis Team, Research Center for Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan.
3 Division of Hematology, Department of Internal Medicine, Jichi Medical School, Shimotsuke, Tochigi, Japan
4 Division of Stem Cell Regulation, Center for Molecular Medicine; and Division of Hematology, Department of Internal Medicine, Jichi Medical School, Shimotsuke, Tochigi, Japan
* To whom correspondence should be addressed. E-mail: furuyu{at}jichi.ac.jp.
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Abstract |
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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, while the other 3 species were up-regulated 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 anti-cancer drugs. Among E2F-1-dependent apoptosis-related molecules, E2F-6 specifically inhibited up-regulation of Apaf-1 by competing with E2F-1 for promoter binding. E2F-6 similarly suppressed apoptosis and Apaf-1 up-regulation in primary hematopoietic progenitor cells during cytokine-induced proliferation, but had no effects when they were differentiated. As a result, E2F-6 enhanced the clonogenic growth of CFU-GEMM. These results suggest that E2F-6 provides a failsafe mechanism against loss of hematopoietic progenitor cells during proliferation.
Key Words.
E2F, hematopoietic progenitor cell, apoptosis, transcription
