Modulation of glycoprotein hormone alpha-subunit levels, alkaline phosphatase activity, and DNA replication by antimetabolites in HeLa cultures

Synthesis of the glycoprotein hormone common alpha-subunit and alkaline phosphatase (placental isozyme) has been examined in HeLa S3 cells. A variety of compounds that inhibit DNA synthesis lead to the increased production of both proteins. Experiments presented in this communication were undertaken to determine whether protein induction and DNA synthesis inhibition are coordinated. In general, nucleoside analogs and compounds that alter deoxynucleotide metabolism were good inducers of these ectopic products, whereas agents that altered DNA by intercalation, crosslinking, and covalent modification were poor inducers. The former class of effectors includes 5-bromo-2'-deoxyuridine, 5-fluoro-2'-deoxyuridine, 2'-deoxythymidine, 1-beta-D-arabinofuranosylcytosine, methotrexate, hydroxyurea, N-phosphonoacetyl-L-aspartic acid, and sodium butyrate; and the latter class of compounds includes ethidium bromide, acridine, bleomycin, mitomycin C, cesalin, macromomycin, and cis-diamminedichloroplatinum(II). A direct correlation between protein induction and DNA synthesis inhibition is unlikely based on the following observations: (i) for some effectors, the concentrations required to induce alpha-subunit and PAP were significantly different from those necessary to inhibit DNA synthesis; (ii) several agents inhibit DNA replication but do not enhance hormone or enzyme production; (iii) the kinetics of ectopic protein induction were similar for a number of inducers whereas the kinetics of DNA synthesis inhibition elicited by the same compounds were quite different. It is difficult from the data obtained, however, to rule out the possibility that inhibition of DNA synthesis may be required but is not sufficient for protein induction.