Cell Cycle Regulation

Cell Cycle Regulation

• Cell division is a highly regulated process that ensures the proper division of a cell into two daughter cells.
• In order to divide, a eukaryotic somatic cell must double its mass and then apportion its components equally between the two daughter cells.

Phases of the Cell Cycle

• The cell cycle consists of two distinct phases: interphase and M phase.
• Interphase comprises G1 (pre-DNA synthesis), S (DNA synthesis), and G2 (pre-division) phases.
• During interphase, the cell grows, and DNA is replicated.
• G1 phase: Cells are released from mitosis into G1 phase, where RNAs and proteins are synthesized, but there is no DNA replication.
• S phase: The initiation of DNA replication marks the transition from G1 phase to the period of S phase, during which the total content of DNA increases from the diploid value of 2n to the fully replicated value of 4n.
• G2 phase: The period from the end of S phase until mitosis is called G2 phase, during which the cell has two complete diploid sets of chromosomes.

G0 Phase

• G0 phase (quiescence) is a phase where cells are not in the cell cycle but have the potential for division.
• Cells can enter G1 from the quiescent state G0 if they are proliferating, or are otherwise activated by mitogenic stimuli.

Cyclins and CDKs

• Cyclins are a family of cell cycle regulatory proteins categorized as D, E, A, or B cyclins, which are expressed to regulate specific phases of the cell cycle.
• Cyclin concentrations rise and fall throughout the cell cycle due to synthesis and degradation.
• D-type cyclins (cyclins 01, 02, and 03) are G1 regulators that are critical for progression through the restriction point.
• CDKs (cyclin-dependent kinases) are activated by binding to their partner cyclins and are negatively regulated by CDK inhibitors.
• CDKs are serine/threonine kinases that phosphorylate substrate proteins on serine and threonine amino acid residues, changing the activation status of regulatory proteins.

Specific CDKs and Cyclins

• CDK2 is responsible for activating target proteins involved in movement from G1 to S (S phase transition) and initiation of DNA synthesis.
• CDK1 targets activated proteins critical for the initiation of mitosis.
• Cyclin E is important in G1 and associates with CDK2 to regulate late G1 phase and the induction of DNA synthesis in early S phase.
• Cyclin A replaces cyclin E as the partner of CDK2, controlling DNA synthesis and replication in the S phase, and then associates with CDK1 to promote entry into the M phase.
• Cyclin B replaces cyclin A, and the cyclin B/CDK1 complex triggers mitosis.

Cell Cycle and Cancer

• Cell cycle-related genes are usually mutated in tumors, leading to unregulated cell proliferation and tumor growth.
• Unregulated expression of cyclins or CDKs is a direct cause of some cancers, as these events elicit cell proliferation independent of normal extracellular stimuli, or promote the bypass of checkpoints that are designed to prevent the propagation of genomic damage.

G1 Checkpoint

• The G1 checkpoint ensures that nuclear synthesis of DNA does not begin until all the appropriate cellular growth has occurred during G1.
• Tumor suppressor proteins, such as retinoblastoma (RB) protein, halt cell cycle progression within G1 when continued growth is not needed or is undesirable or when DNA is damaged.
• Mutated versions of tumor suppressor genes encode proteins that permit cell cycle progression at inappropriate times.