MgcRacGAP is involved in the control of growth and differentiation of hematopoietic cells

In a search for key molecules that prevent murine M1 leukemia cells from un dergoing interleukin (IL)-6-induced differentiation into macrophages, we is olated 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 differe ntiation of M1 cells into macrophage lineages. We also isolated a full-leng th human MgcRacGAP cDNA, which encodes an additional N-terminal polypeptide of 105 amino acid residues compared with the previously published human Mg cRacGAP. In human HL-60 leukemic cells, overexpression of the full-length f orm of human MgcRacGAP alone induced growth suppression and macrophage diff erentiation associated with hypervacuolization and de novo expression of th e myelomonocytic marker CD14, Analyses using a GAP-inactive mutant and 2 de letion mutants of MgcRac-GAP indicated that the GAP activity was dispensabl e, but the myosin-like domain and the cysteine rich domain were indispensab le for growth suppression and macrophage differentiation. The present resul ts indicated that MgcRacGAP plays key roles in controlling growth and diffe rentiation of hematopoietic cells through mechanisms other than regulating Pac GTPase activity. (Blood, 2000;96:2116-2124) (C) 2000 by The American So ciety of Hematology.