第10章細胞の増殖

The second group of cell-cycle regulatory molecules are negative regulators, which stop the cell cycle. Remember that in positive regulation, active molecules cause the cycle to progress.

The best understood negative regulatory molecules are retinoblastoma protein (Rb), p53, and p21. Retinoblastoma proteins are a group of tumor-suppressor proteins common in many cells. We should note here that the 53 and 21 designations refer to the functional molecular masses of the proteins (p) in kilodaltons (a dalton is equal to an atomic mass unit, which is equal to one proton or one neutron or 1 g/mol). Much of what is known about cell-cycle regulation comes from research conducted with cells that have lost regulatory control. All three of these regulatory proteins were discovered to be damaged or non-functional in cells that had begun to replicate uncontrollably (i.e., became cancerous). In each case, the main cause of the unchecked progress through the cell cycle was a faulty copy of the regulatory protein.

Rb, p53, and p21 act primarily at the G₁ checkpoint. p53 is a multi-functional protein that has a major impact on the commitment of a cell to division because it acts when there is damaged DNA in cells that are undergoing the preparatory processes during G₁. If damaged DNA is detected, p53 halts the cell cycle and then recruits specific 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 Cdk/cyclin complexes. 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, which largely monitors cell size, exerts its regulatory influence on other positive regulator proteins. In the active, dephosphorylated state, Rb binds to proteins called transcription factors, most commonly, E2F (Figure 10.14). Transcription factors “turn on” specific genes, allowing the production of proteins encoded by that gene. When Rb is bound to E2F, production of proteins necessary for the G₁/S transition is blocked. As the cell increases in size, Rb is slowly phosphorylated until it becomes inactivated. Rb releases E2F, 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.”

Each step of the cell cycle is monitored by internal controls called checkpoints. There are three major checkpoints in the cell cycle: one near the end of G₁, a second at the G₂/M transition, and the third during metaphase. Positive regulator molecules allow the cell cycle to advance to the next stage of cell division. Negative regulator molecules monitor cellular conditions and can halt the cycle until specific requirements are met.