Tuesday, January 31, 2023

Cyclins and CDKs Cell Cycle Regulation


A cell can switch from G0, or cell cycle arrest, to G1 once cells have attained a critical size. For multicellular organisms, growth factors and mitogens, which are substances encouraging cell division, need to be present. For unicellular organisms, nutrients must be adequate in surroundings. Once G1 is initiated, Cyclin D is synthesized and drives the G1/S phase transition.
In eukaryotes, Cyclin D binds with CDK 4 and CDK 6. These two complexes can partially phosphorylate retinoblastoma tumour suppressor protein, or Rb for short. Rb is bound to E2F, a transcription factor. When the CD-CDK4 and CD-CDK6 complexes partially phosphorylate Rb, it loosens its grip on E2F. E2F can then activate transcription of the cyclin E gene. Cyclin E binds CDK2, and this complex fully phosphorylates Rb, completing its inactivation.
Cyclin E also phosphorylates p27Kip1, an inhibitor of Cyclin D. Phosphorylation of p27Kip1 tags it for degradation. Degradation of this protein promotes expression of cyclin A. E2F also promotes transcription of cyclin A by removing the repressor molecule cell-cycle-responsive element (or CCRE) from the promotor, allowing the cell to enter S phase. The action of E2F on Cyclin A expression is part of a negative feedback loop, since the Cyclin A-CDK2 complex phosphorylates E2F, preventing it from removing the repressor molecule.
Cyclin A is the ONLY cyclin that plays a role in regulation of two cell cycle stages. It can activate two CDKs – CDK2 and CDK1. When Cyclin A forms a complex with CDK2, it allows the cell to progress to S phase. Meanwhile, binding of Cyclin A to CDK1 allows entry into M phase.
During S phase, Cyclin A resides in the nucleus. It directs the initiation and completion of DNA replication. Critically, Cyclin A ensures that DNA replication only occurs ONCE per cell cycle by preventing assembly of excessive replication complexes. How does it accomplish this?
Well, remember how Cyclin E is around at the end of G1? One way in which it helps the cell move into S phase is by initiating assembly of the pre-replication complex. This complex is needed for DNA replication to occur, and forms at the origin of replication. However, Cyclin A also associates with CDK2, and replaces Cyclin E. Once the Cyclin A-CDK2 complex concentration reaches a critical threshold, assembly of the pre-replication complex is terminated. The Cyclin A-CDK2 complex also regulates DNA replication by phosphorylating certain DNA replication machinery components.
Later in the S phase, Cyclin A also forms a complex with CDK1, remaining bound until late in the G2 phase, when it is replaced by cyclin B. The Cyclin A-CDK1 complex is believed to aid in activation and stabilization of the Cyclin B-CDK1 complex before being ubiquitinated. This degradation of the Cyclin A-CDK1 complex induces mitotic exit – in other words, the end of mitosis.
Cyclin B is a mitotic cyclin which binds to CDK1 to form the maturation promoting factor, or mitosis promoting factor – abbreviated MPF. The concentration of MPF rises until mitosis, until its concentration falls abruptly due to degradation of Cyclin B. High concentrations of Cyclin B are necessary for cells to enter M phase, and low concentrations are needed to exit M phase.



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