CELLULAR-RESPONSES IN MOUSE LEUKEMIA-L1210 CELLS MADE RESISTANT TO DEOXYADENOSINE

Recent studies have implicated nucleotides in diverse and unexpected f unctions related to p53 levels, p53-dependent G(0)/G(1) cell cycle arr est, and the role of dATP in the activation of the caspase-induced apo ptosis. Using deoxyadenosine-resistant L1210 cells (ED2 and Y8) that h ad ribonucleotide reductase that was not sensitive to inhibition by dA TP and also exhibited other metabolic alterations, the properties of t hese cells with respect to the role(s) of nucleotides in these functio ns were explored. In the ED2 and Y8 cells that did not express p53 pro tein, the pools of UTP, CTP, ATP, and GTP were markedly decreased. The decreased cellular levels of UTP and CTP did not result in these cell s being more sensitive to either PALA or acivicin. The ED2 and Y8 cell s did not block in G(0)/G(1) in response to PALA treatment even though the basal cellular concentrations of UTP and CTP were reduced 50 to 8 0%. While it has been shown that dATP in combination with cytochrome c is involved in the apoptotic pathway, the concentration of exogenous deoxyadenosine required to induce apoptosis in the parental L1210 cell s was far in excess of the concentration required to inhibit cell grow th. Deoxyadenosine did not cause an increase in apoptosis in the deoxy adenosine-resistant Y8 cells. These data suggest that the new roles as cribed to nucleotides may be specific for the particular cell type und er very specific conditions. (C) 1998 Academic Press.