(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 ␤1, or the growth inhibitory corticosteroid dexamethasone, cyclin G2 mRNA levels were increased in a time-dependent manner 5-14-fold over control cell levels. Proliferation signals promote the coordinated progression of a cell through the cell division cycle. In eukaryotes this process is controlled by the sequential formation, activation, and inhibition of cyclin-cyclin-dependent kinase (CDK) 1 complexes (1). Active cyclin-CDK complexes phosphorylate specific targets such as the tumor suppressor RB, various transcription factors, DNA polymerase ␣, and cytoskeletal proteins (2) and thus trigger progression through the cell cycle. The levels of many cyclins oscillate during the cell cycle and act as rate-limiting positive regulators of CDK activity. Mammalian cyclins are classified into different types based on their structural similarity, functional period in the cell division cycle, and regulated expression (1, 3, 4). 12 different cyclins in mammalian cells (cyclins A-I, some with multiple subtypes) have been identified (1, 5-7) either functionally or through an ϳ110-amino acid homologous region essential for cyclin-CDK complex formation (8 -10) referred to as the cyclin box (3, 11). Cyclin-CDK activity is also subject to regulation by CDK inhibitors (CDKIs) such as p15INK4 and p16 INK4, p21 WAF1/CIP1, and p27 KIP1 which, in response to negative stimuli, bind cyclin-CDK complexes and block cell cycle progression (5, 12). In addition to participation in cellular proliferation, CDKs and cyclin-CDK pairs may participate in processes not directly related to cell cycle regulation as evidenced by Pho80-Pho85 cyclin-CDK participation in yeast phosphate metabolism (13,14), the involvement of p35⅐CDK5 in promoting neurite outgrowth (15-17), the association of the cyclin H/CDK7 pair in the TFIIH transcription factor complex (18,19), and the cyclin C/CDK8 and SRB10/11 cyclin-CDK regulation of RNA polymerase II (20,21).We studied the effects of stimulatory and inhibitory signals on cell cycle components expressed in B lymphocytes representative of two different maturation stages of development. A robust immune system has to deliver specific and effective immune responses to foreign antigens and yet be immunologically tolerant of self-antigens. Such tolerance is achieved because T and B cells pass through stages in their development when ligation of their antigen receptors by self-antigens results in negative regulatory signals that induce either unresponsiveness and functional inactivation (clonal anergy) or their physical elimination (clonal deletion) (22-2...

The overt effects of the anti-cancer drugs cisplatin (cis-DDP) and taxol appear to be DNA modification and microtubule stabilization respectively, yet the mechanisms by which these drugs elicit tumor cell death are not well understood. In this report cell sensitivities to cis-DDP and taxol were accurately determined as a function of cell proliferation and cell cycle stage. Quiescent fibroblasts restimulated to synchronously enter the cell cycle become maximally sensitive to cis-DDP immediately preceding DNA synthesis, and resistance increases with onset of DNA synthesis. Mid-log proliferating cells were separated into progressive stages of the cell cycle by centrifugal elutriation or by double thymidine (dThd) block. Cells staged by either method are maximally sensitive to cis-DDP in G1, just prior to the onset of DNA synthesis and minimally sensitive in peak DNA synthesis, with entry into S phase resulting in a 2-fold decrease in sensitivity. Cells that remained blocked at the G1/S phase boundary during cis-DDP treatment remain maximally sensitive after release. Sensitivity to taxol increases at 2 points: transiently during transition of normal cells from quiescence to proliferation and steadily as proliferating cells progress from early G1 to late G2. This 3-fold increase in taxol sensitivity through the cell cycle is rapidly reversed upon cell division. Synchronous cells treated with either drug at points of maximum sensitivity initiate apoptotic DNA fragmentation 12-14 hr post-exposure to drug.