Functions of Cyclin E
Like all cyclin family members, cyclin E forms a complex with cyclin-dependent kinase (CDK2). Cyclin E/CDK2 regulates multiple cellular processes by phosphorylating numerous downstream proteins.
Cyclin E/CDK2 plays a critical role in the G1 phase and in the G1-S phase transition. Cyclin E/CDK2 phosphorylates retinoblastoma protein (Rb) to promote G1 progression. Hyper-phosphorylated Rb will no longer interact with E2F transcriptional factor, thus release it to promote expression of genes that drive cells to S phase through G1 phase. Cyclin E/CDK2 also phosphorylates p27 and p21 during G1 and S phases, respectively. Smad3, a key mediator of TGF-β pathway which inhibits cell cycle progression, can be phosphorylated by cyclin E/CDK2. The phosphorylation of Smad3 by cyclin E/CDK2 inhibits its transcriptional activity and ultimately facilitates cell cycle progression. CBP/p300 and E2F-5 are also substrates of cyclin E/CDK2. Phosphorylation of these two proteins stimulates the transcriptional events during cell cycle progression. Cyclin E/CDK2 can phosphorylate p220(NPAT) to promote histone gene transcription during cell cycle progression.
Apart from the function in cell cycle progression, cyclin E/CDK2 plays a role in the centrosome cycle. This function is performed by phosphorylating nucleophosmin (NPM). Then NPM is released from binding to an unduplicated centrosome, thereby triggering duplication. CP110 is another cyclin E/CDK2 substrate which involves in centriole duplication and centrosome separation. Cyclin E/CDK2 has also been shown to regulate the apoptotic response to DNA damage via phosphorylation of FOXO1.
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