Methylated oxypurines and induction of differentiation of murine erythroleukemia cells.

Murine erythroleukemia cell lines derived from Friend virus infected mice can be induced to differentiate in vitro by numerous agents. Among these compounds are certain naturally occurring purines such as hypoxanthine or 1-methylhypoxanthine. We have extended these studies to other modified oxypurines and have identified some areas of cell regulation with which they may be interacting. Monomethylated derivatives of guanine, hypoxanthine or xanthine are active as inducers of differentiation. Excluding hypoxanthine, the parent oxypurines guanine and xanthine are ineffective in inducing differentiation. The dimethyl- and trimethylxanthine derivatives are also inactive as inducers. The methylated oxypurines are not metabolized to nucleotides by the cell and, therefore, probably do not interact with nucleic acid synthesis directly. We have investigated one cellular process of possible regulatory significance with which they do interact. ADP-ribosylation has been implicated in control of gene expression and differentiation. The methylated oxypurines inhibit this reaction, as measured in permeabilized cells, in the same concentration range at which they are effective as inducers of differentiation. Additionally, 1-methylguanine and 7-methylguanine decrease incorporation of mannose and glucosamine into glycoprotein and into dolichol-oligosaccharide precursors. These effects may be related to cell surface alterations observed during differentiation.