CYCLIN G2 IS UP-REGULATED DURING GROWTH-INHIBITION AND B-CELL ANTIGENRECEPTOR-MEDIATED CELL-CYCLE ARREST

Human cyclin G2 together with its closest homolog cyclin G1 defines a novel family of cyclins (Horne, M. C., Goolsby, G. L., Donaldson, K. L ., Tran, D., Neubauer, M., and Wahl, A. F. (1996) J. Biol. Chem. 271, 6050-6061), Cyclin G2 is highly expressed in the immune system where i mmunologic tolerance subjects self-reactive lymphocytes to negative se lection and clonal deletion via apoptosis. Here we investigated the ef fect of growth inhibitory signals on cyclin G2 mRNA abundance in diffe rent maturation stage-specific murine B cell lines. Upon treatment of wild type and p53 null B cell lines with the negative growth factor, t ransforming growth factor beta 1, or the growth inhibitory corticoster oid dexamethasone, cyclin G2 mRNA levels were increased in a time-depe ndent manner 5-14-fold over control cell levels. Unstimulated immature B cell lines (WEHI-231 and CH31) and unstimulated or IgM B cell recep tor (BCR)-stimulated mature B cell lines (BAL-17 and CH12) rapidly pro liferate and express low levels of cyclin G2 mRNA. In contrast, BCR-st imulated immature B cell lines undergo growth arrest and coincidentall y exhibit an similar to 10-fold increase in cyclin G2 transcripts and a decrease in cyclin D2 message. Costimulation of WEHI-231 and CH31 ce lls with calcium ionophores and protein kinase C agonists partially mi mics anti-IgM stimulation and elicits a strong up-regulation of cyclin G2 mRNA and down-regulation of cyclin D2 mRNA. Signaling mutants of W EHI-231 that are deficient in the phosphoinositide signaling pathway a nd consequently resistant to the BCR stimulus-induced growth arrest di d not display a significant increase in cyclin G2 or decrease in cycli n D2 mRNAs when challenged with anti-IgM antibodies, The two polyclona l activators lipopolysaccharide and soluble gp39, which inhibit the gr owth arrest response of immature B cells, suppressed cyclin G2 mRNA ex pression induced by BCR stimulation. These results suggest that in mur ine B cells responding to growth inhibitory stimuli cyclin G2 may be a key negative regulator of cell cycle progression.