Abstract
HL-60 promyelocytic leukemic cells have been demonstrated to differentiate in association with depletion of guanine ribonucleotide pools induced by inhibitors of the enzyme IMP dehydrogenase. We have asked whether GTP depletion is indeed causal of HL-60 cell maturation induced by the IMP dehydrogenase inhibitor mycophenolic acid (MPA) and have compared the effects of MPA on cellular metabolism with those of other differentiating agents. Cells grown in the presence of 2 μM MPA were 85 ± 6% differentiated on day 4 of culture. GTP pools were reduced to <20% of control values by 1 hr and remained low over the 4 day incubation period. Repletion of guanine nucleotide pools within 24 hr of initiation of the cuture by exogenous guanosine in the presence of MPA prevented differentiation in wild type but not in HPRT-deficient HL-60 cells. There was no depletion of GTP associated with other differentiating agents and no reversal of differentiation with guanosine. MPA treatment did not result in significant alterations in intracellular cAMP, but did decrease cGMP to 50% of control levels at 24 hrs. There were no changes in 32P-labelled protein patterns on autoradiographs of two dimensional protein gels after MPA exposure. We conclude that depletion of guanine nucleotides is causally related to the HL-60 differentiation induced by IMP dehydrogenase inhibitors but not by other inducers of differentiation of these cells.
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