10.8:
Negative Regulator Molecules
Several proteins negatively regulate the cell cycle to prevent replication from occurring before cells are ready.
During G1 if a cell's DNA is damaged, the protein P53 recruits enzymes to repair the DNA before the cell transitions to S-phase.
P53 also stimulates the production of the CDK inhibitor, P21, which binds to CDK cyclin complexes inhibiting their activity and arresting the cell cycle.
If DNA damage is too much to overcome, P53 can prompt apoptosis, cell death, to prevent duplication of damaged DNA.
Another protein, retinoblastoma protein or Rb, can slow the cell cycle by binding to transcription factors such as E2F to block the transcription of genes necessary for the G1 to S transition.
Once the cell grows to a sufficient size for division, Rb is phosphorylated and becomes inactive, releases E2F, and these genes can now be transcribed and translated into enzymes required for S-phase.
10.8:
Negative Regulator Molecules
Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
Three of the best-understood negative regulators are p53, p21, and retinoblastoma protein (Rb). The regulatory roles of each of these proteins were discovered after faulty copies were found in cells with uncontrolled replication (i.e., cancer). These proteins exert most of their regulatory effects at the G1 checkpoint early in the cell cycle.
P53 strongly influences a cell’s commitment to divide. It responds to DNA damage by discontinuing the cell cycle and summoning enzymes to repair the damage. If the DNA damage is irreparable, p53 can prevent the cell from proceeding through the cell cycle by inducing apoptosis, or cell death.
An increase in p53 triggers the production of p21. P21 prevents the cell from transitioning from the G1 to the S phase of the cell cycle by binding to CDK/cyclin complexes, inhibiting their positive regulatory actions.
Rb negatively regulates the cell cycle by acting on different positive regulators, mainly in response to cell size. Active (dephosphorylated) Rb binds to transcription factors, preventing them from initiating gene transcription and, hence, protein production.
When Rb is bound to the transcription factor E2F, it inhibits the synthesis of proteins needed to transition from the G1 to the S phase. As the cell becomes larger, Rb is gradually phosphorylated until it is inactivated and detaches from E2F. E2F can then activate genes that produce the proteins needed to proceed to the next cell cycle stage.
Suggested Reading
Beckerman, Rachel, and Carol Prives. “Transcriptional Regulation by P53.” Cold Spring Harbor Perspectives in Biology 2, no. 8 (August 1, 2010): a000935. [Source]