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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-04-1177.
Submitted April 18, 2002
Accepted June 27, 2002
GATA-2 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
Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Section of Gene Function and Regulation, Institute of Cancer Research, London, United Kingdom
Department of Molecular Oncology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Center for TARA and Institute of Basic Medical Institute, University of Tsukuba, Tsukuba, Ibaragi, Japan
Division of Cellular Therapy, Advanced Clinical Research Center, University of Tokyo, Minato-ku, Tokyo, Japan
* Corresponding author; email: matumura{at}bldon.med.osaka-u.ac.jp.
GATA-2 is considered to be essential for the development, maintenance and/or 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/ER) into 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 downregulation 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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