Altered expression of beta-globin, transferrin receptor, and ornithine decarboxylase in Friend murine erythroleukemia cells inhibited by alpha-difluoromethylornithine

Abstract

alpha-Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC) and restricts the proliferation and differentiation of Friend murine erythroleukemia cells. We have studied the effect of this compound on the expression of ODC, transferrin receptor (TFR), and beta-globin during normal cellular proliferation and dimethylsulfoxide-induced terminal differentiation. Elevated RNA levels for ODC were observed during both normal Friend murine erythroleukemia cell division and replication associated with terminal differentiation, but these transcripts decreased as the cells ceased proliferating. However, in the presence of DFMO the levels of ODC remained elevated even when the cells had stopped dividing; this appears to be a feedback mechanism to overcome the effects of the inhibitor. TFR expression paralleled regular cell division and was curtailed when replication was reduced by DFMO. However, the inhibitor was unable to prevent the differentiation associated maintenance of TFR levels, well after proliferation terminated. While DFMO was able to restrict differentiation and hemoglobin synthesis, it did not inhibit the dimethylsulfoxide-induced expression of beta-globin RNA. We concluded that the block in differentiation caused by DFMO occurs along some pathway(s) other than the activation of beta-globin or TFR.