REGULATION OF CYCLIN G1 DURING MURINE HEPATIC REGENERATION FOLLOWING DIPIN-INDUCED DNA-DAMAGE

Cyclin G1 has been linked to both positive and negative growth regulat ion. The expression of cyclin G1 is induced by transforming growth fac tor beta(1) and p53, as well as by multiple mitogenic stimuli in mamma lian cells in culture. However, the physiological role of cyclin G1 re mains unclear. To examine the cell-cycle regulation of cyclin G1 in vi vo, two models of coordinated cell proliferation induced by partial he patectomy (PH) in the presence or absence of DNA damage were used. To introduce DNA damage, mice were treated with the alkylating drug, 1,4- bis[N,N'-di(ethylene)-phosphamide]piperazine (Dipin) 2 hours before PH . Cell-cycle progression was monitored by 5-bromo-2-deoxyuridine (BrdU ) incorporation into the DNA, the frequency of mitoses, the expression of cell-cycle control genes, and by flow cytometry. Dipin treatment r esulted in cell-cycle arrest at the G2/M boundary without affecting G0 /G1 and G1/S transitions. While the hepatocytes progressively entered G2 phase arrest, the cyclin G1 mRNA and protein levels increased more than five- and eightfold, respectively. Cyclin G1 had a nuclear locali zation in all interphase cells with clear absence from nucleoli. In co ntrast, during mitosis, cyclin G1 was undetectable by immunohistochemi stry. Taken together, our data provide evidence for a putative role of cyclin G1 in G2/M checkpoint control.