Cyclin G2 is up-regulated during growth inhibition and B cell antigen receptor-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 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.
Horne
M C
MC
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121, USA. mchorne@facstaff.wisc.edu
Donaldson
K L
KL
Goolsby
G L
GL
Tran
D
D
Mulheisen
M
M
Hell
J W
JW
Wahl
A F
AF
D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D003001:Cloning, Molecular; D056766:Cyclin G1; D056767:Cyclin G2; D016213:Cyclins / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D010703:Phorbol Esters / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D016415:Sequence Alignment; D015854:Up-Regulation
C101593:CCNG2 protein, human; C534703:Ccng1 protein, mouse; D056766:Cyclin G1; D056767:Cyclin G2; D016213:Cyclins; D018076:DNA, Complementary; D008070:Lipopolysaccharides; D010703:Phorbol Esters; D010716:Phosphatidylinositols; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D002118:Calcium