FIGURE 1.

Principles of cell cycle in the beta cell. Beta cells predominantly reside in a quiescent, non-mitotic G0 phase. Upon the mitogenic stimuli, the assembly of Cyclins D and CDK4/6 complex and consequent pRb inactivation via hyperphosphorylation trigger the cell cycle entry. Once the E2F transcription factors are released from the pRb restraining, they enhance expression of the cell cycle promoting genes, including the late Cyclins and CDKs. The activities of different Cyclins-CDK complexes gradually replace each other with the cell cycle progression, so that each Cyclins-CDK complex is dominant during different cell cycle phases. In G1, Cyclins D-CDK4/6 regulate cell growth and preparation for DNA replication. In the S phase, Cyclins E-CDK2 complexes control DNA replication. Whereas in phase G2, Cyclins A with CDK1 are driving preparation for the cell division. Finally, in phase M, complexes of Cyclins B-CDK1 regulate the cell division. The promoting activities of Cyclins-CDK complexes are negatively regulated by the cell cycle inhibitors. Families of Ink4 and Cip/Kip inhibitors restrain the early and late Cyclins-CDKs complexes, respectively. On the way towards division, the cell must encounter several STOP checkpoints whereby the cell state, DNA integrity and the surrounding conditions are checked. Cells which do not pass the checkpoint, are blocked from cell cycle progression until the conditions improve or, in an irresolvable situation, undergo apoptosis. The inner circles on Figure 1 represent the commonly used proliferation markers: Ki67, BrdU, pHH3. Intensity of the violet color corresponds to the abundance of the marker at a given phase, with white color indicating absence of the marker and dark violet – the highest detectability.