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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-04-1177.
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Blood, 15 November 2002, Vol. 100, No. 10, pp. 3512-3520
HEMATOPOIESIS
GATA-2/estrogen receptor chimera regulates cytokine-dependent
growth of hematopoietic cells through accumulation of
p21WAF1 and p27Kip1 proteins
Sachiko Ezoe,
Itaru Matsumura,
Soichi Nakata,
Karin Gale,
Katsuhiko Ishihara,
Naoko Minegishi,
Takashi Machii,
Toshio Kitamura,
Masayuki Yamamoto,
Tariq Enver, and
Yuzuru Kanakura
From the Department of Hematology/Oncology and
Molecular Oncology, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka, Japan; Center for TARA and Institute of Basic
Medical Institute, University of Tsukuba, 1-1-1 Tennodai, Tsukuba,
Japan; Division of Cellular Therapy, Advanced Clinical Research Center,
Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo,
Japan; and Section of Gene Function and Regulation, Institute of Cancer
Research, Chester Beatty Laboratories, London, United Kingdom.
GATA-2 is considered to be essential for the development,
maintenance, and function of hematopoietic stem cells (HSCs). However, it was also reported that GATA-2 inhibits the growth of HSCs. To
examine the role of GATA-2 in the growth of hematopoietic cells, we
introduced an estradiol-inducible form of GATA-2 (GATA-2/estrogen receptor [ER]) into interleukin 3 (IL-3)-dependent cell lines, Ba/F3, 32D, and FDC-P1. Estradiol-induced GATA-2 suppressed
c-myc mRNA expression and inhibited IL-3-dependent growth
in these clones. As for this mechanism, GATA-2 was found to inhibit
ubiquitin/proteasome-dependent degradation of p21WAF1 and
p27Kip1 and to induce their accumulation by repressing the
expression of Skp2 and Cul1, both of which are components of the
ubiquitin ligase for p21WAF1 and p27Kip1.
Overexpression of c-myc restored the expression of Skp2 and Cul1 mRNA, reduced the amounts of p21WAF1 and
p27Kip1 proteins, and canceled GATA-2-induced growth
suppression, suggesting that down-regulation of c-myc
expression may be primarily responsible for GATA-2-induced growth
suppression. Next, we transduced retrovirus containing GATA-2/ER into
murine bone marrow mononuclear cells (MNCs) and stem/progenitor
(Sca-1+Lin ) cells. GATA-2/ER suppressed
cytokine-dependent growth of MNCs and
Sca-1+Lin cells by about 70%, which was also
accompanied by the reduced expression of c-myc, Skp2, and
Cul1 mRNA and the accumulation of p21WAF1 and
p27Kip1 proteins. In addition, the amount of GATA-2 protein
was found to decline in hematopoietic stem/progenitor cells that were
promoted to enter cell cycle by the stimulation with cytokines. These
results suggest that GATA-2 may regulate expression levels of
p21WAF1 and p27Kip1, thereby contributing to
the quiescence of hematopoietic stem/progenitor cells.
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