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Blood, 15 September 2000, Vol. 96, No. 6, pp. 2116-2124
HEMATOPOIESIS
MgcRacGAP is involved in the control of growth and
differentiation of hematopoietic cells
Toshiyuki Kawashima,
Koichi Hirose,
Takaya Satoh,
Azusa Kaneko,
Yasuo Ikeda,
Yoshito Kaziro,
Tetsuya Nosaka, and
Toshio Kitamura
From Department of Hematopoietic Factors and Department
of Clinical Oncology, The Institute of Medical Science, University of
Tokyo, Minato-ku, Tokyo, Japan; Faculty of Bioscience and
Biotechnology, Tokyo Institute of Technology, Yokohama, Japan; and
Division of Hematology, Department of Internal Medicine, School of
Medicine, Keio University, Tokyo, Japan.
In a search for key molecules that prevent murine M1 leukemia cells
from undergoing interleukin (IL)-6-induced differentiation into
macrophages, we isolated an antisense complementary DNA (cDNA) that
encodes full-length mouse MgcRac-GTPase-activating protein (GAP)
through functional cloning. Forced expression of this antisense cDNA
profoundly inhibited IL-6-induced differentiation of M1 cells into
macrophage lineages. We also isolated a full-length human MgcRacGAP
cDNA, which encodes an additional N-terminal polypeptide of 105 amino
acid residues compared with the previously published human MgcRacGAP.
In human HL-60 leukemic cells, overexpression of the full-length form
of human MgcRacGAP alone induced growth suppression and macrophage
differentiation associated with hypervacuolization and de novo
expression of the myelomonocytic marker CD14. Analyses using a
GAP-inactive mutant and 2 deletion mutants of MgcRacGAP indicated that
the GAP activity was dispensable, but the myosin-like domain and the
cysteine-rich domain were indispensable for growth suppression
and macrophage differentiation. The present results indicated that
MgcRacGAP plays key roles in controlling growth and differentiation of
hematopoietic cells through mechanisms other than regulating Rac GTPase activity.
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