Cyclin G2 Is Up-regulated during Growth Inhibition and B Cell Antigen Receptor-mediated Cell Cycle Arrest

Abstract

(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...

Nodal enhances the activity of FoxO3a and its synergistic interaction with Smads to regulate cyclin G2 transcription in ovarian cancer cells

“…Several studies have shown that CCNG2 mRNA levels and/or protein levels are upregulated by growth inhibitory signals, including TGF-b (Horne et al, 1997) and downregulated by oncogenic pathways, such as PI3K-AKT in murine NIH 3T3 cells (Martinez-Gac et al, 2004), HER2, c-jun NH2-terminal kinase and the mammalian target of rapamycin/p70S6K (Le et al, 2007), and estrogen signaling (Stossi et al, 2006) in breast cancer cells. In immortalized ovarian surface epithelial and ovarian cancer cells, Nodal increased CCNG2 mRNA and protein levels, as well as CCNG2 protein stability (Xu et al, 2008).…”

“…CCNG2 has a short half-life and it is quickly degraded through the ubiquitinproteasome pathway (Xu et al, 2008), providing a way by which arrested or quiescent cells may re-enter the cell cycle. Ectopic expression of the CCNG2 inhibited cell proliferation and induced cell cycle arrest in murine B cells (Horne et al, 1997), HEK293, Chinese hamster ovary cells (Bennin et al, 2002) and several cancer cell lines (Kim et al, 2004;Le et al, 2007;Xu et al, 2008). In breast cancer cells, CCNG2 expression is inhibited by HER2 through multiple intracellular pathways, including phosphoinositide 3-kinase (PI3K), c-jun NH2-terminal kinase and the mammalian target of rapamycin (Le et al, 2007).…”

Cyclin G2 is a centrosome-associated nucleocytoplasmic shuttling protein that influences microtubule stability and induces a p53-dependent cell cycle arrest

“…Moreover, ectopic cyclin G1 is primarily a nuclear protein, whereas tagged cyclin G2 is largely cytoplasmic [1,21,22]. Developmental expression and tissue distribution of cyclin G1 and G2 also differ [7,8,21]. In lymphocytes cyclin G1 expression is constitutive throughout the cell cycle, whereas cyclin G2 expression oscillates, peaking in late S and early G2 phase of the cell cycle [7,8].…”

“…In contrast to the cyclin G1 gene [19,20], the cyclin G2 gene is not a transcriptional target of p53 [7][8][9]21]. Moreover, ectopic cyclin G1 is primarily a nuclear protein, whereas tagged cyclin G2 is largely cytoplasmic [1,21,22].…”

“…Despite structural similarities, some cyclins and CDKs are associated with functions not directly linked to cell cycle progression, e.g., transcription and neurite outgrowth [4][5][6]. Cyclin G2, (G2) is an unconventional cyclin [7,8] expressed at modest levels in proliferating cells, peaking during the late S/early G 2 -phase, that is significantly upregulated as cells exit the cell cycle in response to DNA damage and receptor mediated negative signaling in B-lymphocytes [7][8][9]. Recent reports of differential microarray analyses consistently point to G2 upregulation in parallel with cell cycle inhibition during responses to diverse growth inhibitory signals, such as heat shock, oxidative stress, hypoxia and differentiation, further supporting the hypothesis that G2 has cell cycle inhibitory functions [10][11][12][13][14][15][16].…”