Alternative titles; symbols
HGNC Approved Gene Symbol: CCNE1
Cytogenetic location: 19q12 Genomic coordinates (GRCh38): 19:29,811,991-29,824,312 (from NCBI)
Koff et al. (1991) isolated a novel human cyclin, named cyclin E, by complementation of a triple cln deletion in Saccharomyces cerevisiae. The deduced protein contains 395 amino acids and has a calculated molecular mass of 45 kD. Lew et al. (1991) also identified cyclin E.
Mumberg et al. (1997) isolated a CCNE1 splice variant, which they termed cyclin ET (third isoform of cyclin E), that lack 45 amino acids and has a molecular mass of 43 kD. The authors noted that another isoform, cyclin ES (second isoform of cyclin E), has a 49-amino acid internal deletion within the cyclin box. Cyclin ET contains an intact cyclin box but is unable to function as a G1 cyclin in yeast, indicating that the cyclin box is required but not sufficient for CCNE1 activity. The cyclin ET variant was expressed in all cell types tested, and was expressed before other isoforms in the G0 to S cycle and peaked in the G1 phase.
Koff et al. (1991) found that human cyclin E showed genetic interactions with the yeast Cdc28 gene, suggesting that it functions at the G1/S transition, or START, by interacting with the Cdc28 protein. They identified CDC2 (116940) and CDK2 (116953) as human genes that could interact with cyclin E to perform START in yeast containing a Cdc28 mutation.
Keyomarsi et al. (1994) demonstrated that breast cancers, as well as some other solid tumors, show severe quantitative and qualitative alterations in cyclin E protein production. In breast cancer, the alterations in cyclin E expression became progressively worse with increasing stage and grade of the tumor, suggesting its potential use as a prognostic marker.
Cyclin-dependent kinase (CDK) activation requires association with cyclins (e.g., CCNE1) and phosphorylation by CAK (CCNH; 601953), and leads to cell proliferation. Inhibition of cellular proliferation occurs upon association of CDK inhibitor (e.g., CDKN1B; 600778) with a cyclin-CDK complex. Sheaff et al. (1997) showed that expression of CCNE1-CDK2 at physiologic levels of ATP results in phosphorylation of CDKN1B at thr187, leading to elimination of CDKN1B from the cell and progression of the cell cycle from G1 to S phase. At low ATP levels, the inhibitory functions of CDKN1B are enhanced, thereby arresting cell proliferation.
Hinchcliffe et al. (1999) developed a Xenopus egg extract arrested in S phase that supported repeated assembly of daughter centrosomes. Multiple rounds of centrosome reproduction were blocked by selective inactivation of CDK2-cyclin E and were restored by addition of purified CDK2-cyclin E. Confocal microscopy revealed that cyclin E was localized at the centrosome. The authors concluded that CDK2-cyclin E activity is required for centrosome duplication during S phase and that these results suggested a mechanism that could coordinate centrosome reproduction with cycles of DNA synthesis and mitosis.
Spruck et al. (1999) demonstrated that constitutive cyclin E overexpression in both immortalized rat embryo fibroblasts and human breast epithelial cells results in chromosome instability. In contrast, analogous expression of cyclin D1 (CCND1; 168461) or A (123835) does not increase the frequency of chromosome instability. Cyclin E-expressing cells that exhibit chromosome instability have normal centrosome numbers. However, constitutive overexpression of cyclin E impairs S-phase progression, indicating that aberrant regulation of this process may be responsible for the chromosome instability observed. Spruck et al. (1999) concluded that downregulation of cyclin E-CDK2 kinase activity following the G1/S-phase transition may be necessary for the maintenance of karyotypic stability.
Moberg et al. (2001) demonstrated that cyclin E is bound directly by AGO (606278), which probably targets its ubiquitin-mediated degradation.
Keyomarsi et al. (2002) investigated cyclin E as a determinant of the virulence and metastatic potential of breast cancer cells. In normal dividing cells, cyclin E regulates the transition from the G1 phase to the S phase, and a high level of cyclin E protein accelerates the transition through the G1 phase. They assayed for cyclin E in tumor tissue from 395 patients with breast cancer and correlated the findings with follow-up (median 6.4 years). Levels of total cyclin E and low-molecular weight cyclin E in tumor tissue, as measured by Western blot assay, correlated strongly with survival in patients with breast cancer. The hazard ratio for death from breast cancer for patients with high total cyclin E levels as compared with those with low total cyclin E levels was 13.3, or about 8 times as high as the hazard ratios associated with other independent clinical and pathologic risk factors.
Matsumoto and Maller (2004) identified 20 amino acids in cyclin E as a centrosomal localization signal (CLS) essential for both centrosomal targeting and promoting DNA synthesis. Expressed wildtype, but not mutant, CLS peptides localized on the centrosome, prevented endogenous cyclin E and cyclin A from localizing to the centrosome, and inhibited DNA synthesis. Ectopic cyclin E localized to the centrosome and accelerated S phase entry even with mutations that abolished Cdk2 binding, but not with a mutation in the CLS. Matsumoto and Maller (2004) concluded that cyclin E has a modular centrosomal-targeting domain essential for promoting S phase entry in a Cdk2-independent manner.
Using bioinformatics and molecular biologic approaches, Kaddar et al. (2009) identified CAPRIN1 (601178), HMGA1 (600701), and CCNE1 as targets of microRNA-16 (MIR16; see 609704). Luciferase analysis demonstrated that MIR16 interacted with the 3-prime UTRs of CAPRIN1, HMGA1, and CCNE1 and that it downregulated expression of these proteins, which are involved in cell proliferation, in cancer cell lines.
The CCNE gene was mapped to 19q12-q13 by Demetrick et al. (1995) using fluorescence in situ hybridization (FISH). Ashworth et al. (1995) positioned the CCNE gene at 19q13.1 by cosmid contig assembly methods and by FISH. Li et al. (1996) mapped the CCNE gene to 19q12 by FISH. Johnson et al. (1996) found that the Ccne gene maps to mouse chromosome 7.
Geng et al. (1999) generated a mouse strain in which the coding sequences of the Ccnd1 gene were deleted and replaced by those of human CCNE1. In the tissues and cells of these mice, the expression pattern of human CCNE1 faithfully reproduced that normally associated with mouse Ccnd1. The replacement of Ccnd1 by CCNE1 rescued all phenotypic manifestations of Ccnd1 deficiency and restored normal development in Ccnd1-dependent tissues. Thus, Geng et al. (1999) concluded that CCNE1 can functionally replace CCND1. Furthermore, this study suggested that CCNE1 is the major downstream target of CCND1.
Geng et al. (2003) created mice deficient in cyclin E1, cyclin E2 (CCNE2; 603775), or both. Cyclin E1-null mice were born at the expected mendelian ratio and appeared normal throughout their lives, whereas cyclin E2-deficient males had reduced fertility associated with reduced testicular size and greatly reduced sperm counts. Double-knockout mice died prior to embryonic day 11.5 and showed growth retardation, but no gross abnormalities or pathologic lesions. Examination of extraembryonal tissues revealed profoundly abnormal placentas, with severely impaired endoreplication of trophoblast giant cells. Endoreplication in double-knockout megakaryocytes was also severely impaired. Cyclin E-null cells proliferated actively under conditions of continuous cell cycling, but they were unable to reenter the cell cycle following G0 arrest. Molecular analysis revealed that cells lacking cyclin E failed to normally incorporate MCM proteins (see MCM2; 116945) into DNA replication origins during G0 to S progression.
Ashworth, L. K., Batzer, M. A., Brandriff, B., Branscomb, E., de Jong, P., Garcia, E., Garnes, J. A., Gordon, L. A., Lamerdin, J. E., Lennon, G., Mohrenweiser, H., Olsen, A. S., Slezak, T., Carrano, A. V. An integrated metric physical map of human chromosome 19. Nature Genet. 11: 422-427, 1995. [PubMed: 7493023] [Full Text: https://doi.org/10.1038/ng1295-422]
Demetrick, D. J., Matsumoto, S., Hannon, G. J., Okamoto, K., Xiong, Y., Zhang, H., Beach, D. H. Chromosomal mapping of the genes for the human cell cycle proteins cyclin C (CCNC), cyclin E (CCNE), p21 (CDKN1) and KAP (CDKN3). Cytogenet. Cell Genet. 69: 190-192, 1995. [PubMed: 7698009] [Full Text: https://doi.org/10.1159/000133960]
Geng, Y., Whoriskey, W., Park, M. Y., Bronson, R. T., Medema, R. H., Li, T., Weinberg, R. A., Sicinski, P. Rescue of cyclin D1 deficiency by knockin cyclin E. Cell 97: 767-777, 1999. [PubMed: 10380928] [Full Text: https://doi.org/10.1016/s0092-8674(00)80788-6]
Geng, Y., Yu, Q., Sicinska, E., Das, M., Schneider, J. E., Bhattacharya, S., Rideout, W. M., III, Bronson, R. T., Gardner, H., Sicinski, P. Cyclin E ablation in the mouse. Cell 114: 431-443, 2003. [PubMed: 12941272] [Full Text: https://doi.org/10.1016/s0092-8674(03)00645-7]
Hinchcliffe, E. H., Li, C., Thompson, E. A., Maller, J. L., Sluder, G. Requirement of Cdk2-cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts. Science 283: 851-854, 1999. [PubMed: 9933170] [Full Text: https://doi.org/10.1126/science.283.5403.851]
Johnson, D. K., Stubbs, L. J., DeLoia, J. A. The mouse cyclin E maps to chromosome 7. Mammalian Genome 7: 245, 1996. [PubMed: 8833259] [Full Text: https://doi.org/10.1007/s003359900278]
Kaddar, T., Rouault, J.-P., Chien, W. W., Chebel, A., Gadoux, M., Salles, G., Ffrench, M., Magaud, J.-P. Two new miR-16 targets: caprin-1 and HMGA1, proteins implicated in cell proliferation. Biol. Cell 101: 511-524, 2009. [PubMed: 19250063] [Full Text: https://doi.org/10.1042/BC20080213]
Keyomarsi, K., O'Leary, N., Molnar, G., Lees, E., Fingert, H. J., Pardee, A. B. Cyclin E, a potential prognostic marker for breast cancer. Cancer Res. 54: 380-385, 1994. [PubMed: 7903908]
Keyomarsi, K., Tucker, S. L., Buchholz, T. A., Callister, M., Ding, Y., Hortobagyi, G. N., Bedrosian, I., Knickerbocker, C., Toyofuku, W., Lowe, M., Herliczek, T. W., Bacus, S. S. Cyclin E and survival in patients with breast cancer. New Eng. J. Med. 347: 1566-1575, 2002. Note: Erratum: New Eng. J. Med. 348: 186 only, 2003. [PubMed: 12432043] [Full Text: https://doi.org/10.1056/NEJMoa021153]
Koff, A., Cross, F., Fisher, A., Schumacher, J., Leguellec, K., Philippe, M., Roberts, J. M. Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family. Cell 66: 1217-1228, 1991. [PubMed: 1833068] [Full Text: https://doi.org/10.1016/0092-8674(91)90044-y]
Lew, D. J., Dulic, V., Reed, S. I. Isolation of three novel human cyclins by rescue of G1 cyclin (cln) function in yeast. Cell 66: 1197-1206, 1991. [PubMed: 1833066] [Full Text: https://doi.org/10.1016/0092-8674(91)90042-w]
Li, H., Lahti, J. M., Valentine, M., Saito, M., Reed, S. I., Look, A. T., Kidd, V. J. Molecular cloning and chromosomal localization of the human cyclin C (CCNC) and cyclin E (CCNE) genes: deletion of the CCNC gene in human tumors. Genomics 32: 253-259, 1996. [PubMed: 8833152] [Full Text: https://doi.org/10.1006/geno.1996.0112]
Matsumoto, Y., Maller, J. L. A centrosomal localization signal in cyclin E required for Cdk2-independent S phase entry. Science 306: 885-888, 2004. [PubMed: 15514162] [Full Text: https://doi.org/10.1126/science.1103544]
Moberg, K. H., Bell, D. W., Wahrer, D. C. R., Haber, D. A., Hariharan, I. K. Archipelago regulates cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature 413: 311-316, 2001. [PubMed: 11565033] [Full Text: https://doi.org/10.1038/35095068]
Mumberg, D., Wick, M., Burger, C., Haas, K., Funk, M., Muller, R. Cyclin ET, a new splice variant of human cyclin E with a unique expression pattern during cell cycle progression and differentiation. Nucl. Acids Res. 25: 2098-2105, 1997. [PubMed: 9153308] [Full Text: https://doi.org/10.1093/nar/25.11.2098]
Sheaff, R. J., Groudine, M., Gordon, M., Roberts, J. M., Clurman, B. E. Cyclin E-CDK2 is a regulator of p27(Kip1). Genes Dev. 11: 1464-1478, 1997. [PubMed: 9192873] [Full Text: https://doi.org/10.1101/gad.11.11.1464]
Spruck, C. H., Won, K.-A., Reed, S. I. Deregulated cyclin E induces chromosome instability. Nature 401: 297-300, 1999. [PubMed: 10499591] [Full Text: https://doi.org/10.1038/45836]