Abstract
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 immunologic tolerance subjects self-reactive lymphocytes to negative selection and clonal deletion via apoptosis. Here we investigated the effect of growth inhibitory signals on cyclin G2 mRNA abundance in different maturation stage-specific murine B cell lines. Upon treatment of wild-type and p53 null B cell lines with the negative growth factor, transforming growth factor beta1, or the growth inhibitory corticosteroid dexamethasone, cyclin G2 mRNA levels were increased in a time-dependent manner 5-14-fold over control cell levels. Unstimulated immature B cell lines (WEHI-231 and CH31) and unstimulated or IgM B cell receptor (BCR) -stimulated mature B cell lines (BAL-17 and CH12) rapidly proliferate and express low levels of cyclin G2 mRNA. In contrast, BCR-stimulated immature B cell lines undergo growth arrest and coincidentally exhibit an approximately 10-fold increase in cyclin G2 transcripts and a decrease in cyclin D2 message. Costimulation of WEHI-231 and CH31 cells with calcium ionophores and protein kinase C agonists partially mimics anti-IgM stimulation and elicits a strong up-regulation of cyclin G2 mRNA and down-regulation of cyclin D2 mRNA. Signaling mutants of WEHI-231 that are deficient in the phosphoinositide signaling pathway and consequently resistant to the BCR stimulus-induced growth arrest did not display a significant increase in cyclin G2 or decrease in cyclin D2 mRNAs when challenged with anti-IgM antibodies. The two polyclonal activators lipopolysaccharide and soluble gp39, which inhibit the growth arrest response of immature B cells, suppressed cyclin G2 mRNA expression induced by BCR stimulation. These results suggest that in murine B cells responding to growth inhibitory stimuli cyclin G2 may be a key negative regulator of cell cycle progression.
Highlights
Proliferation signals promote the coordinated progression of a cell through the cell division cycle
Up-regulation of Cyclin G2 and Down-regulation of Cyclin D2 mRNAs Coincident with B cell receptor (BCR)-induced Growth Arrest and Apoptosis—We investigated whether other growth inhibitory signals elicit an up-regulation of cyclin G2 mRNA in B lymphocytes
We present compounding evidence that expression of cyclin G2 is up-regulated in B cells during responses to negative signaling, and we present arguments for its possible role as a negative regulator of the cell cycle
Summary
Proliferation signals promote the coordinated progression of a cell through the cell division cycle. To further investigate the relationship of p53 to cyclin G2 mRNA expression and examine the cell cycle position-dependent expression of murine cyclin G2, Northern blot analysis was performed on fractionated cells from the p53 wild-type, IgMϩ immature B cell line WEHI-231, and the p53 null, IgMϩ mature B cell line BAL-17 (Fig. 2C).
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