regulation of cell cycle G1/S phase transition

Definition

Target type: biologicalprocess

Any signaling pathway that modulates the activity of a cell cycle cyclin-dependent protein kinase to modulate the switch from G1 phase to S phase of the cell cycle. [GO_REF:0000058, GOC:mtg_cell_cycle, GOC:TermGenie]

The G1/S phase transition, a crucial checkpoint in the cell cycle, ensures that cells only progress into DNA replication (S phase) when conditions are favorable and all prerequisites are met. This tightly controlled process involves a complex interplay of regulatory proteins, signaling pathways, and external cues.

**Key Players:**

* **Cyclins and Cyclin-Dependent Kinases (CDKs):** These protein pairs act as master regulators of the cell cycle. G1 cyclins (Cyclin D1, D2, D3) and CDK4/6 complexes are activated early in G1, driving cell growth and promoting the accumulation of critical proteins necessary for S phase entry.
* **Retinoblastoma Protein (Rb):** Rb acts as a brake on cell cycle progression. In its hypophosphorylated state, Rb binds and inhibits transcription factors (E2F), preventing the expression of genes required for S phase entry.
* **E2F Transcription Factors:** These factors regulate the expression of genes essential for DNA replication and other S phase processes.
* **Checkpoint Kinases (Chk1 and Chk2):** These kinases are activated in response to DNA damage or replication stress, leading to cell cycle arrest in G1 and preventing progression to S phase.

**Regulation of G1/S Transition:**

1. **Growth Factor Stimulation:** Growth factors bind to their receptors, activating signaling pathways like the MAPK and PI3K pathways. These pathways promote the transcription of genes encoding G1 cyclins and CDK4/6, ultimately leading to their accumulation in the cell.
2. **CDK4/6 Activation:** CDK4/6 complexes are activated by association with G1 cyclins. Activated CDK4/6 phosphorylate Rb, leading to its inactivation.
3. **Rb Inactivation and E2F Activation:** As Rb becomes phosphorylated, it loses its ability to bind and inhibit E2F transcription factors. This allows E2F to activate the transcription of genes necessary for S phase entry, including those encoding DNA replication proteins and other cell cycle regulators.
4. **G1/S Checkpoint Activation:** Before committing to S phase, cells undergo a checkpoint to assess their readiness for DNA replication. This checkpoint ensures sufficient nutrients, proper cell size, and the absence of DNA damage. If any of these conditions are not met, the G1/S checkpoint prevents progression into S phase.
5. **S Phase Entry:** Once all conditions are met and the G1/S checkpoint is passed, cells enter S phase, initiating DNA replication.

**Factors Influencing G1/S Transition:**

* **Growth Factors:** Growth factors like epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) stimulate cell proliferation and drive the G1/S transition.
* **Nutrients:** Adequate nutrient availability is crucial for cell growth and DNA replication.
* **Oxygen:** Oxygen is essential for cellular metabolism and DNA replication.
* **DNA Damage:** DNA damage triggers a checkpoint response that arrests the cell cycle in G1 to allow for DNA repair before entering S phase.
* **Cellular Stress:** Various forms of cellular stress can also trigger cell cycle arrest in G1.

**Consequences of Dysregulation:**

Dysregulation of the G1/S checkpoint can lead to uncontrolled cell proliferation, a hallmark of cancer. Mutations in genes involved in this checkpoint, such as Rb, p53, and CDK inhibitors, can contribute to tumorigenesis.

**In summary, the G1/S transition is a tightly regulated process that ensures proper timing and coordination of cell cycle events, preventing uncontrolled proliferation and ensuring genomic integrity. This critical checkpoint is controlled by a complex network of signaling pathways and regulatory proteins that respond to both internal and external cues, ensuring that cells only enter S phase when conditions are favorable.**'
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Proteins (1)

Compounds (3)