Upregulation of Metallothionein-1G Accelerates G1/S Transition in the Growth Phase of Acute Promyelocytic Leukemia NB4 Cells.

Downregulation of the myeloid master regulator Spi1/PU.1 plays a pivotal role in leukemogenesis, and we previously showed that Spi1/PU.1 directly represses metallothionein (MT)-1G through the epigenetic activity of PU.1. Furthermore, we recently demonstrated that overexpression of MT-1G inhibits retinoic acid-induced differentiation of acute promyelocytic leukemia NB4 cells. As PU.1 is a master regulator of growth and differentiation in myeloid cells, we examined its effects on cell proliferation of MT-1G-overexpressing NB4 (NB4MTOE) cells in the present study. Although there were no significant differences in total viable cell numbers between NB4MTOE cells and control cells during the time course examined, the proportion of S-phase cells was obviously increased in all NB4MTOE cells at 16-24 h after serum stimulation. Consistent with these findings, real-time PCR analyses revealed marked increases in the expression of cyclin E (G1/S-phase cyclin) and cyclin A (S-phase cyclin) in NB4MTOE cells during the same time period. Furthermore, NB4MTOE cells were significantly resistant to cytosine arabinoside (Ara-C), an S-phase-specific chemotherapeutic drug. Collectively, these findings suggest a role for MT-1G in G1/S transition during the growth phase of NB4 cells.