Cyclin E1 Explained

G1/S-specific cyclin-E1 is a protein that in humans is encoded by the CCNE1 gene.^[1]

Function

The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance through the cell cycle. Cyclins function as regulators of CDK. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of CDK2, whose activity is required for cell cycle G1/S transition. This protein accumulates at the G1-S phase boundary and is degraded as cells progress through S phase. Overexpression of this gene has been observed in many tumors, which results in chromosome instability, and thus may contribute to tumorigenesis. This protein was found to associate with, and be involved in, the phosphorylation of NPAT protein (nuclear protein mapped to the ATM locus), which participates in cell-cycle regulated histone gene expression and plays a critical role in promoting cell-cycle progression in the absence of pRB. Two alternatively spliced transcript variants of this gene, which encode distinct isoforms, have been described. Two additional splice variants were reported but detailed nucleotide sequence information is not yet available.^[2]

Interactions

Cyclin E1 has been shown to interact with:

• CDC25A,^[3]
• CDKN1B,
• CUL3^[4]
• Cdk1,^[5]
• Cyclin-dependent kinase 2,^{[6] [5] [7] [8] [9]}
• HERC5,^[10]
• P21,^[7]
• Retinoblastoma-like protein 2,^{[11] [12]} and
• SMARCA4.^{[11] [13]}

See also

• Cyclin E
• Cyclin E/Cdk2

Further reading

• Akita H . [Prognostic importance of altered expression of cell cycle regulators in lung cancer] . Nippon Rinsho . Suppl 5 . 267–71 . 2003 . 12101670 . 60 .
• Mazumder S, DuPree EL, Almasan A . A dual role of cyclin E in cell proliferation and apoptosis may provide a target for cancer therapy. . . 4 . 1 . 65–75 . 2004 . 14965268 . 1307511 . 10.2174/1568009043481669 .
• Hinds PW, Mittnacht S, Dulic V, Arnold A, Reed SI, Weinberg RA . Regulation of retinoblastoma protein functions by ectopic expression of human cyclins. . Cell . 70 . 6 . 993–1006 . 1992 . 1388095 . 10.1016/0092-8674(92)90249-C . 30799229 .
• Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan DO, Franza BR, Roberts JM . Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle. . Science . 257 . 5077 . 1689–94 . 1992 . 1388288 . 10.1126/science.1388288 . 1992Sci...257.1689K .
• Koff A, Cross F, Fisher A, Schumacher J, Leguellec K, Philippe M, Roberts JM . Human cyclin E, a new cyclin that interacts with two members of the CDC2 gene family. . Cell . 66 . 6 . 1217–28 . 1991 . 1833068 . 10.1016/0092-8674(91)90044-Y . 38910227 .
• Demetrick DJ, Matsumoto S, Hannon GJ, Okamoto K, Xiong Y, Zhang H, Beach DH . 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 . 3–4 . 190–2 . 1995 . 7698009 . 10.1159/000133960 .
• Ohtsubo M, Theodoras AM, Schumacher J, Roberts JM, Pagano M . Human cyclin E, a nuclear protein essential for the G1-to-S phase transition. . Mol. Cell. Biol. . 15 . 5 . 2612–24 . 1995 . 7739542 . 230491 . 10.1128/mcb.15.5.2612.
• Sewing A, Rönicke V, Bürger C, Funk M, Müller R . Alternative splicing of human cyclin E. . J. Cell Sci. . (Pt 2) . 581–8 . 1994 . 8207080 . 107 . 2 . 10.1242/jcs.107.2.581 .
• Dyson N, Dembski M, Fattaey A, Ngwu C, Ewen M, Helin K . Analysis of p107-associated proteins: p107 associates with a form of E2F that differs from pRB-associated E2F-1. . J. Virol. . 67 . 12 . 7641–7 . 1993 . 8230483 . 238233 . 10.1128/JVI.67.12.7641-7647.1993.
• Li Y, Graham C, Lacy S, Duncan AM, Whyte P . The adenovirus E1A-associated 130-kD protein is encoded by a member of the retinoblastoma gene family and physically interacts with cyclins A and E. . Genes Dev. . 7 . 12A . 2366–77 . 1994 . 8253383 . 10.1101/gad.7.12a.2366 . free .
• Xu X, Burke SP . Roles of active site residues and the NH2-terminal domain in the catalysis and substrate binding of human Cdc25. . J. Biol. Chem. . 271 . 9 . 5118–24 . 1996 . 8617791 . 10.1074/jbc.271.9.5118 . free .
• Ohtani K, DeGregori J, Nevins JR . Regulation of the cyclin E gene by transcription factor E2F1. . Proc. Natl. Acad. Sci. U.S.A. . 92 . 26 . 12146–50 . 1996 . 8618861 . 40313 . 10.1073/pnas.92.26.12146 . free .
• Geng Y, Eaton EN, Picón M, Roberts JM, Lundberg AS, Gifford A, Sardet C, Weinberg RA . Regulation of cyclin E transcription by E2Fs and retinoblastoma protein. . Oncogene . 12 . 6 . 1173–80 . 1996 . 8649818 .
• Poon RY, Jiang W, Toyoshima H, Hunter T . Cyclin-dependent kinases are inactivated by a combination of p21 and Thr-14/Tyr-15 phosphorylation after UV-induced DNA damage. . J. Biol. Chem. . 271 . 22 . 13283–91 . 1996 . 8662825 . 10.1074/jbc.271.22.13283 . free .
• Chen J, Saha P, Kornbluth S, Dynlacht BD, Dutta A . Cyclin-binding motifs are essential for the function of p21CIP1. . Mol. Cell. Biol. . 16 . 9 . 4673–82 . 1996 . 8756624 . 231467 . 10.1128/MCB.16.9.4673.
• Li H, Lahti JM, Valentine M, Saito M, Reed SI, Look AT, Kidd VJ . 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 . 2 . 253–9 . 1997 . 8833152 . 10.1006/geno.1996.0112 .
• Won KA, Reed SI . Activation of cyclin E/CDK2 is coupled to site-specific autophosphorylation and ubiquitin-dependent degradation of cyclin E. . EMBO J. . 15 . 16 . 4182–93 . 1996 . 8861947 . 452142 . 10.1002/j.1460-2075.1996.tb00793.x.
• Sala A, Kundu M, Casella I, Engelhard A, Calabretta B, Grasso L, Paggi MG, Giordano A, Watson RJ, Khalili K, Peschle C . Activation of human B-MYB by cyclins. . Proc. Natl. Acad. Sci. U.S.A. . 94 . 2 . 532–6 . 1997 . 9012818 . 19547 . 10.1073/pnas.94.2.532 . 1997PNAS...94..532S . free .
• Mumberg D, Wick M, Bürger C, Haas K, Funk M, Müller R . Cyclin ET, a new splice variant of human cyclin E with a unique expression pattern during cell cycle progression and differentiation. . Nucleic Acids Res. . 25 . 11 . 2098–105 . 1997 . 9153308 . 146711 . 10.1093/nar/25.11.2098 .

Notes and References

1. Lew DJ, Dulić V, Reed SI . Isolation of three novel human cyclins by rescue of G1 cyclin (Cln) function in yeast . Cell . 66 . 6 . 1197–206 . October 1991 . 1833066 . 10.1016/0092-8674(91)90042-W . 12166415 .
2. Web site: Entrez Gene: CCNE1 cyclin E1.
3. Xu X, Burke SP . Roles of active site residues and the NH2-terminal domain in the catalysis and substrate binding of human Cdc25 . J. Biol. Chem. . 271 . 9 . 5118–24 . March 1996 . 8617791 . 10.1074/jbc.271.9.5118. free .
4. Singer JD, Gurian-West M, Clurman B, Roberts JM . Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells . Genes Dev. . 13 . 18 . 2375–87 . September 1999 . 10500095 . 317026 . 10.1101/gad.13.18.2375.
5. Koff A, Giordano A, Desai D, Yamashita K, Harper JW, Elledge S, Nishimoto T, Morgan DO, Franza BR, Roberts JM . Formation and activation of a cyclin E-cdk2 complex during the G1 phase of the human cell cycle . Science . 257 . 5077 . 1689–94 . September 1992 . 1388288 . 10.1126/science.1388288. 1992Sci...257.1689K .
6. Connor MK, Kotchetkov R, Cariou S, Resch A, Lupetti R, Beniston RG, Melchior F, Hengst L, Slingerland JM . CRM1/Ran-mediated nuclear export of p27(Kip1) involves a nuclear export signal and links p27 export and proteolysis . Mol. Biol. Cell . 14 . 1 . 201–13 . January 2003 . 12529437 . 140238 . 10.1091/mbc.E02-06-0319 .
7. McKenzie PP, Danks MK, Kriwacki RW, Harris LC . P21Waf1/Cip1 dysfunction in neuroblastoma: a novel mechanism of attenuating G0-G1 cell cycle arrest . Cancer Res. . 63 . 13 . 3840–4 . July 2003 . 12839982 .
8. Mayer C, Zhao J, Yuan X, Grummt I . mTOR-dependent activation of the transcription factor TIF-IA links rRNA synthesis to nutrient availability . Genes Dev. . 18 . 4 . 423–34 . February 2004 . 15004009 . 359396 . 10.1101/gad.285504 .
9. Boudrez A, Beullens M, Groenen P, Van Eynde A, Vulsteke V, Jagiello I, Murray M, Krainer AR, Stalmans W, Bollen M . NIPP1-mediated interaction of protein phosphatase-1 with CDC5L, a regulator of pre-mRNA splicing and mitotic entry . J. Biol. Chem. . 275 . 33 . 25411–7 . August 2000 . 10827081 . 10.1074/jbc.M001676200 . free .
10. Mitsui K, Nakanishi M, Ohtsuka S, Norwood TH, Okabayashi K, Miyamoto C, Tanaka K, Yoshimura A, Ohtsubo M . A novel human gene encoding HECT domain and RCC1-like repeats interacts with cyclins and is potentially regulated by the tumor suppressor proteins . Biochem. Biophys. Res. Commun. . 266 . 1 . 115–22 . December 1999 . 10581175 . 10.1006/bbrc.1999.1777 .
11. Shanahan F, Seghezzi W, Parry D, Mahony D, Lees E . Cyclin E associates with BAF155 and BRG1, components of the mammalian SWI-SNF complex, and alters the ability of BRG1 to induce growth arrest . Mol. Cell. Biol. . 19 . 2 . 1460–9 . February 1999 . 9891079 . 116074 . 10.1128/mcb.19.2.1460.
12. Li Y, Graham C, Lacy S, Duncan AM, Whyte P . The adenovirus E1A-associated 130-kD protein is encoded by a member of the retinoblastoma gene family and physically interacts with cyclins A and E . Genes Dev. . 7 . 12A . 2366–77 . December 1993 . 8253383 . 10.1101/gad.7.12a.2366. free .
13. Wong AK, Shanahan F, Chen Y, Lian L, Ha P, Hendricks K, Ghaffari S, Iliev D, Penn B, Woodland AM, Smith R, Salada G, Carillo A, Laity K, Gupte J, Swedlund B, Tavtigian SV, Teng DH, Lees E . BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines . Cancer Res. . 60 . 21 . 6171–7 . November 2000 . 11085541 .