Introduction

• Regulatory molecules either promote progress of the cell to the next phase (positive regulation) or halt the cycle (negative regulation)

• Regulator molecules may act individually, or they can influence the activity or production of other regulatory proteins.

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

• 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 regulate the cell cycle only when they are tightly bound to Cdks. To be fully active, the Cdk/cyclin complex must also be phosphorylated in specific locations.

• The levels of Cdk proteins are relatively stable throughout the cell cycle; however, the concentrations of cyclin fluctuate and determine when Cdk/cyclin complexes form.

• The different cyclins and Cdks bind at specific points in the cell cycle and thus regulate different checkpoints.

• Since the cyclic fluctuations of cyclin levels are based on the timing of the cell cycle and not on specific events, regulation of the cell cycle usually occurs by either the Cdk molecules alone or the Cdk/cyclin complexes.

• Without a specific concentration of fully activated cyclin/Cdk complexes, the cell cycle cannot proceed through the checkpoints.

Negative Regulation of the Cell Cycle

• Negative regulatory molecules are retinoblastoma protein (Rb), p53, and p21

• Retinoblastoma proteins: a group of tumor-suppressor proteins common in many cells

• Rb, p53, and p21 act primarily at the G1 checkpoint

• If damaged DNA is detected, p53 halts the cell cycle and recruits enzymes to repair the DNA.

  • If the DNA cannot be repaired, p53 can trigger apoptosis, or cell death, 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 exerts its regulatory influence on other positive regulator proteins.

• Rb mainly monitors cell size.

• In the active, dephosphorylated state, Rb binds to proteins called transcription factors, most commonly, E2F.

  • 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.”