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...

(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...

Mutations in the nuclear matrix protein Matrin 3 (MATR3) have been identified in amyotrophic lateral sclerosis and myopathy. To investigate the mechanisms underlying MATR3 mutations in neuromuscular diseases and efficiently screen for modifiers of MATR3 toxicity, we generated transgenic MATR3 flies. Our findings indicate that expression of wild‐type or mutant MATR3 in motor neurons reduces climbing ability and lifespan of flies, while their expression in indirect flight muscles (IFM) results in abnormal wing positioning and muscle degeneration. In both motor neurons and IFM, mutant MATR3 expression results in more severe phenotypes than wild‐type MATR3, demonstrating that the disease‐linked mutations confer pathogenicity. We conducted a targeted candidate screen for modifiers of the MATR3 abnormal wing phenotype and identified multiple enhancers involved in axonal transport. Knockdown of these genes enhanced protein levels and insolubility of mutant MATR3. These results suggest that accumulation of mutant MATR3 contributes to toxicity and implicate axonal transport dysfunction in disease pathogenesis.

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