MAGNESIUM RESTRICTION INDUCES GRANULOCYTIC DIFFERENTIATION AND EXPRESSION OF P27(KIP1) IN HUMAN LEUKEMIC HL-60 CELLS

When cultured in Mg restricted medium, human leukemic HL-60 cells deve lop morphological and functional granulocytic differentiation. In 0.03 mM Mg, cells display the distinctive features of differentiation, wit hout appreciable inhibition of proliferation. In 0.01 mM Mg, cells sho w terminal differentiation, accompanied by clear inhibition of prolife ration. Such cells accumulate in the G0/G1 phase and subsequently die via apoptosis, similar to HL-60 cells that have been induced to differ entiate by DMSO. These phenotypic changes are associated with a marked increase in the expression level of the cyclin dependent kinase inhib itor p27(Kip1). Cyclin E expression is also slightly increased in Mg r estricted cells, whereas no changes are observed in the expression lev el of cyclin D1.We also show that during differentiation cell total Mg decreases, whereas [Mg2+](i) increases in both Mg-depleted and DMSO-t reated cells. These data suggest that the maturation process is parall eled by a redistribution of intracellular Mg, leading to a shift from the bound to the free form. These changes could modulate the kinetics of Mg-dependent enzyme(s) that are involved in the control of the diff erentiation pathway. We propose that this model may represent an usefu l tool for the study of the mechanisms of cell differentiation and rel ated events, such as aging and death. J. Cell. Biochem. 70.313-322, 19 98. (C) 1998 Wiley-Liss, Inc.