Cyclin G1 and Cyclin G2 Comprise a New Family of Cyclins with Contrasting Tissue-specific and Cell Cycle-regulated Expression

Abstract

We describe the isolation and characterization of cDNAs encoding full-length human and murine cyclin G1 and a novel human homologue of this cyclin designated cyclin G2. Cyclin G1 is expressed at high levels in skeletal muscle, ovary, and kidney. Following an initial up-regulation from early G 1 to G 1 /S phase, cyclin G1 mRNA is constitutively expressed throughout the cell cycle in T and B cell lines. In contrast, in stimulated peripheral T cells, cyclin G1 mRNA is maximal in early G 1 phase and declines in cell cycle progression. Cyclin G1 levels parallel p53 expression in murine B lymphocytes; however, in several human Burkitt's lymphomas, murine lymphocytes treated with transforming growth factor-␤, early murine embryos, and several tissues of p53 null mice, cyclin G1 levels are either inverse of p53 levels or expressed independent of p53. The cyclin G1 homologue, cyclin G2, exhibits 60% nucleotide sequence identity and 53% amino acid sequence identity with cyclin G1, and like cyclin G1, exhibits closest sequence identity to the cyclin A family. Distinct from cyclin G1, the amino acid sequence for cyclin G2 shows a PESTrich sequence and a potential Shc PTB binding site. Cyclin G2 mRNA is differentially expressed compared to cyclin G1, the highest transcript levels seen in cerebellum, thymus, spleen, prostate, and kidney. In contrast to the constitutive expression of cyclin G1 in lymphocytes, cyclin G2 mRNA appears to oscillate through the cell cycle with peak expression in late S phase.Transitions through the eukaryotic cell division cycle are primarily coordinated by the sequential activation of cyclin-dependent kinases (CDKs) 1 which are, in turn, regulated by subunit associations and phosphorylation (reviewed in Refs. 1-3). The cyclins represent a group of closely related molecules which primarily function at specific stages of the cell cycle as regulators of CDK activity by binding and forming active complexes with specific partner CDKs. This cyclin-CDK association is in part determined by the conserved cyclin region of ϳ110 amino acids referred to as the cyclin box (4 -6). The cyclin box exhibits ϳ30 -50% identity between the different cyclin types, the consensus sequence varying depending on the class and subclass of cyclin (5,7,8). Cyclins have been classified into different groups on the basis of their structural similarity, functional period in the cell division cycle and regulated expression. In addition to providing positive growth control, CDKs and cyclin-CDK pairs may participate in metabolism and signal transduction unrelated to cell cycle as evidenced by pho80-pho85 cyclin-CDK complex participation in yeast phosphate metabolism (9, 10), the expression of CDK5 in nonproliferating brain tissue (11-13), and the SRB10/11 cyclin-CDK regulator of RNA polymerase II (14).To date at least 12 different cyclins in budding yeast, 4 in fission yeast, and 10 in mammalian cells (cyclins A-H with multiple family members for some types) are known, all primarily displaying sequence homology within the cyclin b...

A role of cyclin G in the process of apoptosis

“…We con®rmed that BMP-4 can induce apoptosis in aggregated P19 cells (data not shown). We were interested in determining if cyclin G is a downstream target of BMP-4 for two reasons: (i) as shown above cyclin G shows pro-apoptotic activity in aggregated P19 cells; (ii) it was reported that cyclin G is induced by a related family member, TGF-b (Horne et al, 1996). Therefore, levels of cyclin G protein were examined in aggregated P19 cells after incubation with BMP-4 ( Figure 5).…”

“…Although levels of cyclin G RNA remain constant throughout the cell cycle in actively cycling cells, immunohistochemcal studies have indicated that levels of cyclin G protein decrease to undetectable levels during mitosis (Tamura et al, 1993;Horne et al, 1996;Jensen et al, 1998). It has been reported that overexpression of cyclin G promotes cell growth in the RKO colon carcinoma cell line, suggesting a positive role for cyclin G on the cell cycle (Smith et al, 1997).…”

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

“…Human cyclin G2 (CCNG2) belongs to the 'G' family of unconventional cyclins (Bates et al, 1996;Horne et al, 1996). Unlike other cyclins that function to promote cell cycle progression, CCNG2 has not been detected to form complexes with any cyclin-dependent protein kinases.…”

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

“…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].…”

“…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].…”