Gene family: cyclins; (CCNA CCNB1 CCNB2 CCNC CCND1 CCND2 CCND2P CCND3 CCND3P CCNE CCNF CCNG1 CCNG2 CCNH CCNL1 CCNT1 CCNT2)


IDN

The term cyclin was originally used to describe periodically accumulating mitotic regulators of the p34 protein kinase. They were first identified in cleaving eggs of marine invertebrates, as proteins that accumulated to high levels following the fertilization of eggs and underwent abrupt destruction in mitosis in each synchronous cell division during early embryogenesis (Rosenthal-1980; Evans-1983; Swenson-1986; Standart-1987)."

FUN

The cyclins are involved in regulation of cell division. They act as regulatory subunits of p34-cdc2 and p34-cdc28 protein kinases during the G1/S transition. Cyclins undergo periodic fluctuations during each cell cycle, reaching maximal levels at the G2 to M transition and being rapidly destroyed during mitosis (Rosenthal-1980, Evans-1983, Swenson-1986, Matsushime-1991). The degradation of cyclins is necessary for cell to exit from mitosis (Murray,Kirschner-1989; Wang-1990). The amount of cyclin in the cell has been shown to be regulated post-translationally in invertebrates (Lehner,O'Farrell-1989; Standart-1987; Wang-1990), but the expression of human cyclin B is regulated both during and after transcription (Wang-1990). The cdc2-cyclin complex is a constituent of the maturation promoting factor (Draetta-1989; Brizuela-1989; Draetta, Beach-1989; Labbe-1989; Wang-1990) and cyclins are necessary before it can initiate mitosis and meiosis (Minshull-1989; Meijer-1989; Pines-1987; Murray-1989; Wang-1990). Activation of the maturation promoting factor coincides with maximal histone H1 kinase activity of cdc2 (Meijer-1989; Pines,Hunter-1989; Draetta-1989; Brizuela-1989; Wang-1990) and with the dephosphorylation of its tyrosine residues (Moria-1989; Wang-1990)."

EVO

[1] The cyclins are highly conserved in evolution. Comprehensive amino acid sequence comparison of all cyclin genes was conducted by Xiong-1991. Seventeen published cyclin sequences were aligned using a strategy described by Xiong and Eickbush (Xiong, Eickbush-1990). Effort was made to reach the maximum similarity between sequences with the minimum introduction of insertion/deletions and to include as much sequence as possible. With the exception of CLN cyclins, this alignment contains about 200 amino acid residues that cover most part of the total coding regions of cyclins. There is a conserved domain and some scattered similarities between members of A- and B-type cyclins N-terminal to the aligned region but this is not present in either CLN cyclins or CYCD1 and CYL1, and so they were not included in the alignment. The percent divergence for all pairwise comparisons of the 17 aligned sequences was calculated and used to construct an evolutionary tree of the cyclin gene family using the neighbor-joining method (Saitou, Nei-1987). Because of the lowest similarity of CLN cyclins to the other three classes, authors have rooted this tree at the connection between the CLN cyclins and the others. Phylogenetic analysis shows that on structural grounds cyclin D1 is on a different branch of the evolutionary tree from A-, B-, or CLN-type cyclins. Murine genes closely related to human cyclin D1 have been identified (Matsushime-1991; Xiong-1991). Figure 1. Evolutionary tree of the Cyclin Gene Family. (Length of the horizontal lines reflect divergence. The branch length between the node connecting the CLN cyclins and other cyclins was arbitrary divided.) (from Xiong-1991). 谀哪履哪哪哪哪 CYCA-Hs (human A-type cyclin) 谀哪 滥哪哪哪哪 CYCA-XI (Xenopus A-type cyclin) 谀哪哪哪 滥哪哪哪哪哪哪 CYCA-Ss (clam A-type cyclin) 滥哪哪哪哪哪哪哪哪 CYCA-Dm (Drosophila A-type cyclin) 谀哪 谀哪哪哪穆哪 CYCB1-Hs (human B1-type cyclin) 滥 CYCB1-XI (Xenopus B1-type cyclin) 谀哪哪拇 谀哪穆哪哪 CYCB2-XI (Xenopus B2-type cyclin) 滥 滥哪 CYCB-Ss (clam B-type cyclin) 谀拇 谀拇 滥哪哪履哪 CYCB-Asp (starfish B-type cyclin) 滥哪 滥哪 CYCB-Arp (sea urchin B-type cyclin) 滥哪哪哪哪哪哪哪哪 CYCB-Dm (Drosophila B-type cyclin) 滥哪哪哪哪哪哪哪哪哪哪 CYC13-Sp (S.pombe cdc 13) 滥哪哪哪哪哪哪哪哪哪哪哪哪哪履 CYCD1-Hs (human D1-type cyclin) 滥 CYL1-Mm (murine D1-type cyclin) 谀哪哪哪哪哪哪哪哪哪哪哪哪履 CLN1-Sc (S.cerevisiae cyclin 1) 滥哪拇 滥 CLN2-Sc (S.cerevisiae cyclin 2) 滥哪哪哪哪哪哪哪哪哪哪哪哪哪 CLN3-Sc (S.cerevisiae cyclin 3)
[2] To assess structural and evolutionary relationships between cyclins Xiong & (Xiong-1992) compared the protein sequence of 11 mammalian cyclins. This includes cyclin A, cyclins B1 and B2, six D-type cyclins (three from human and three from mouse), and cyclins E and C (see Figure 2). % Figure 2. Protein sequence homology of mammalian cyclins. % Cyclin A 1.00 Cyclin B1 0.49 1.00 Cyclin B2 0.54 0.67 1.00 Cyclin C 0.21 0.20 0.19 1.00 Cyclin D1 0.40 0.30 0.30 0.22 1.00 Cyclin D2 0.38 0.28 0.29 0.22 0.79 1.00 Cyclin D3 0.40 0.28 0.31 0.20 0.73 0.83 1.00 Cyclin E 0.43 0.42 0.39 0.18 0.38 0.35 0.34 1.00 Cy 0.39 0.30 0.30 0.23 0.98 0.80 0.74 0.36 1.00 Cy 0.39 0.29 0.32 0.19 0.72 0.88 0.75 0.35 0.72 1.00 Cy 0.40 0.27 0.34 0.17 0.63 0.72 0.88 0.31 0.63 0.78 1.00 A B1 B2 C D1 D2 D3 E Cyl1 Cyl2 Cyl3 The three human cyclin D genes share very high similarity over their entire coding region, 60% between D1 and D2, 60% between D2 and D3, and 52% between D1 and D3. The members of the D-type cyclins are more closely related to each other than are members of the B-type cyclins, averaging 78% for three cyclin D genes in the cyclin box versus 57% for two cyclin B genes. These and some other features of D-type cyclins (see GEM:11q133/CCND1) suggests that the separation (emergence) of D-type cyclins occured after that of cyclin B1 (GEM:05q1/CCNB1) from B2 (GEM:00.0/CCNB2). Finally, using the well-characterized mitotic B-type cyclin as an index, the most closely related genes are cyclin A (GEM:04q/CCNA) (average 51%), followed by the E-type (GEM:19q1/CCNE)(40%), D-type (29%), and C-type (GEM:06q21/CCNC) cyclins (20%)."

EAG

[1] Cyclins have been identified in yeast, clam, starfish, sea urchin (Solomon-1988; Goelb-1988), Drosophila murins and variety of other eukaryotes.
[2] In budding yeasts, a separate family of G1 cyclins, represented by CLNs 1,2, and 3, plays an adjunctive role in regulating the G1/S-phase transition, thereby determining the cell's commitment to replicate its chromosomal DNA (Nash-1988; Cross-1988; Hadwiger-1989; Richardson-1989). Mammalian genes related to the yeast CLNs have not been detected by homology screening (Matsushime-1991; Xiong-1991; Motokura-1991; Lew-1991; Koff-1991)."

PAT

Cyclins may interplay with genes involved in tumorigenesis (Wang-1990). Region 12p13 contains sites of several translocations that are associated with specific immunophenotypes of disease, such as acute lymphoblastic leukemia, chronic myelomoncytic leukemia, and acute myeloid leukemia. Particularly, the isochromosome of the short arm of chromosome 12 [i(12p)] is one of a few known consistent chromosomal abnormalities in human solid tumors (see review by Jong-1990) and is seen in 90% of adult testicular germ cell tumors (Samaniego-1990). Region 6p21, on the other hand, has been implicated in the manifestation of chronic lymphoproliferative disorder and leiomyoma (Mitelman-1990). A t(6;9)(p21;q33) chromosome translocation was found as the sole chromosomal anomaly in three unrelated cases; two acute myeloid leukemias and one chronic myelocytic leukemia (Vermaelen-1983; Xiong-1992)."

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