Regulated progression through the cell cycle requires sequential expression of a family of proteins called cyclins. Upon their induction, cyclins form complexes with specific cyclin-dependent kinases (CDKs), creating active holoenzymes that phosphorylate target proteins that are required for cell-cycle progression. In higher eukaryotes, CDKl associated with mitotic cyclins (cyclin A, B1, and B2) controls the G2/M transition, while multiple CDK-cyclin complexes control the GUS transition. Putative G1 cyclins (cyclin C, D, and E) were isolated when human and Drosophila cDNA libraries were used to complement yeast G1 mutants. Among the human G1 cyclins, only cyclin E was shown to fluctuate periodically through the cell cycle. The amounts of cyclin E mRNA, protein, and CDK2-associated protein kinase activity were maximal in late G1 in HeLa cells. Functional analysis suggested that cyclin E is rate-limiting for G1 progression, since overexpression of cyclin E accelerated the GUS transition in mammalian fibroblasts, while microinjection of anti-cyclin E antibodies inhibited this transition. In addition, cyclin E was shown to be required for S phase entry and to specifically induce transcription of S phase genes (DNA polymerase a, PCNA, and two ribonucleotide reductase subunits) in Drosophila. It was also reported that multiple levels of regulation of the cyclin E mRNA, protein, and associated kinase activity are present during the first 24h of zebrafish embryonic development.
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