Positive Regulation of the Cell Cycle

Two groups of proteins, called cyclins and cyclin-dependent kinases (CDKs), are responsible for the progress of the cell through the various checkpoints (Figure 3). The levels of the four cyclin proteins fluctuate throughout the cell cycle in a predictable pattern. Increases in the concentration of cyclin proteins are triggered by both external and internal signals. After the cell moves to the next stage of the cell cycle, the cyclins that were active in the previous stage are degraded.

Cyclins are active only when they are tightly bound to CDKs. When a cyclin is tightly bound to its CDK, it will phosphorylate other proteins (add a phosphate chemical group), which activates the protein by changing its shape. The proteins phosphorylated by cyclin/CDK complexes are involved in advancing the cell to the next phase. Because there are different cyclins present at different points during the cell cycle, different cyclin/CDK complexes regulate different checkpoints. Without a specific concentration of fully activated cyclin/CDK complexes, the cell cycle cannot proceed through the checkpoints.

One sentence summary: Different sets of cyclins bound to CDKs act as positive regulators of the cell cycle because they activate other proteins that help the cell cycle to move forward through the various checkpoints.

Negative Regulation of the Cell Cycle

The second group of cell cycle regulatory molecules are negative regulators. In positive regulation, active molecules such as CDK/cyclin complexes cause the cell cycle to progress. In negative regulation, active molecules halt the cell cycle (Figure 3).

The best understood negative regulatory molecules are retinoblastoma protein (Rb), p53, and p21.  All three of these regulatory proteins were discovered to be damaged or non-functional in cells that had begun to replicate uncontrollably (became cancerous). In each case, the main cause of the unchecked progress through the cell cycle was a faulty copy of one of these regulatory proteins. For this reason, Rb and other proteins that negatively regulate the cell cycle are sometimes called tumor suppressors.

Rb, p53, and p21 act primarily at the G₁ checkpoint, where the cell determines whether it has adequate energy reserves, is large enough, and whether there is damage to the genomic DNA. The p53 protein has a major impact on the commitment of a cell to divide. If damaged DNA is detected at the G₁ checkpoint, p53 halts the cell cycle and recruits enzymes to repair the DNA. If the DNA cannot be repaired, p53 can trigger apoptosis, or cell suicide, to prevent the duplication of damaged chromosomes. As p53 levels rise, the production of p21 is triggered. p21 enforces the halt in the cycle dictated by p53 by binding to and inhibiting the activity of the cyclin/CDK complexes. If cyclin/CDK complexes are inhibited, the cell cycle can’t move forward. As a cell is exposed to more stress, higher levels of p53 and p21 accumulate, making it less likely that the cell will move into the S phase.

Rb exerts its regulatory influence on other positive regulator proteins. Chiefly, Rb monitors cell size. In the active state, Rb binds to proteins called transcription factors. Transcription factors “turn on” transcription of specific genes, allowing the production of proteins encoded by that gene. When Rb is bound to transcription factors, production of proteins necessary for the G₁/S transition is blocked. As the cell increases in size, Rb is slowly inactivated. Rb releases the transcription factors, which can now turn on the gene that produces the transition protein, and this particular block is removed. For the cell to move past each of the checkpoints, all positive regulators must be “turned on,” and all negative regulators must be “turned off.”

One sentence take-homes:

• If the p53 protein detects DNA damage which can’t be repaired, it tells the cell to commit suicide.
• p21 is produced in response to p53 and stops the cell cycle by inhibiting CDK/cyclins.
• Rb blocks production of proteins necessary for the cell cycle to proceed.