There are hundreds of genes that may affect the cell cycle, either directly or acting through complex pathways. The most well understood regulators are the cyclins, the cyclin dependent kinases, TP53 and RB1.
Cyclin Dependent Kinases
Cyclin dependent kinases are a family of kinases which, when activated by binding with a cyclin, lead to progression through the cell cycle. There are numerous kinases responsible for different parts of the cell cycle.
- CDK4 and CDK6 are involved in progression through G1 phase. They bind with cyclin D and phosphorylate RB1.
- CDK2 is activated by cyclin E and is required for progression through the G1/S checkpoint.
- CDK1, or CDC2, was the first described CDK. When bound with cyclin B it promotes progression through the G2/M checkpoint.
Unlike CDKs, cyclins are only produced in the cell at specific points in the cell cycle. This allows the cell to maintain control of the cell cycle. Chromosomal abnormalities and mutations involving cyclins are implicated in carcinogenesis.
- CCND1, 2 and 3 (Cyclin D) are three similar proteins that are upregulated during G1. Translocation of CCND1 from chromosome 11 to 14, adjacent to the promoter for an immunoglobulin, is thought to be an important step in the development of some lymphomas.
- CCNE1 and CCNE2 (Cyclin E) are particularly involved in the G1 / S checkpoint when bound with CDK2. They are regulated by a number of inhibitory cell cycle proteins in the CIP/KIP family. E1 and E2 are expressed in different tissue types.
- CCNA1 and CCNA2 (Cyclin A) are active in S phase and G2. In S phase they bind to CDK2, promoting DNA replication. In G2 phase they bind to CDK1,
- CCNB1 and CCNB2 (Cyclin B) are active at the G2/M checkpoint. B1 is found attached to microtubles and B2 with the Golgi apparatus.
RB1 (Retinoblastoma 1)
RB1 is the gene that codes for retinoblastoma-associated protein. This is a critical component of the cell cycle that binds to transcription factors of the E2F family. By sequestering E2F, RB1 prevents expression of genes that allow the cell to enter and progress through S-phase. Mutation of this gene may lead to increased incidence of childhood malignancy, particularly retinoblastoma, bladder tumours and osteogenic sarcoma.
RB1 was the first identified tumour suppressor gene.
TP53 (Tumour Protein p53)
TP53 is a central gene in cell survival. Its activity increases in response to DNA damage (through ATM/ATR phosphorylation or other methods), extracellular signalling, hypoxia and spindle damage. Increased activity of TP53 leads to cell cycle arrest, increased DNA repair, and/or apoptosis. TP53 is mutated in Li-Fraumeni syndrome, which leads to increased frequency of malignancies.
The function of TP53 is regulated by MDM2, which is normally bound to TP53 to prevent its function. ATM phosphorylates both TP53 and MDM2 in response to DNA damage, leading to deactivation of MDM2 and activation of TP53.