G1/S transition

G1-S cell cycle regulation

Cell Cycle 2-2

Signal transduction v1

RB1

P53 Pathway

G1/S transition is a crucial phase in the cell cycle that marks the transition from the G1 phase, where the cell grows, to the S phase, where DNA replication occurs. This transition is tightly regulated by various proteins and enzymes to ensure that the cell is ready to replicate its DNA and divide. The G1/S transition is a key checkpoint in the cell cycle, ensuring that cells do not replicate damaged DNA or divide under unfavorable conditions.

Regulation of G1/S Transition

The regulation of the G1/S transition involves a complex network of cyclin-dependent kinases (CDKs) and their regulatory subunits, cyclins. The most important of these is the cyclin D-CDK4/6 complex in early G1 and the cyclin E-CDK2 complex in late G1, which phosphorylate the retinoblastoma protein (Rb) and other proteins to promote progression into the S phase.

p53 protein also plays a critical role in the G1/S transition. It can induce cell cycle arrest in response to DNA damage or other stress signals, thus preventing the replication of damaged DNA. p53 acts primarily through the transcriptional activation of the CDK inhibitor p21, which inhibits CDK activity, thereby halting the cell cycle.

Molecular Mechanisms

The molecular mechanisms underlying the G1/S transition involve several key steps: 1. **Cyclin D synthesis** is induced by mitogenic signals, leading to the formation of the cyclin D-CDK4/6 complex. 2. **Rb phosphorylation**: The cyclin D-CDK4/6 complex phosphorylates Rb, partially releasing E2F transcription factors that were bound and inhibited by Rb. 3. **E2F activation**: Free E2F acts as a transcription factor for genes essential for S phase entry, including cyclin E. 4. **Cyclin E-CDK2 activation**: Cyclin E forms a complex with CDK2, which further phosphorylates Rb, completely releasing all E2F. This positive feedback loop ensures the cell's commitment to the S phase. 5. **p53-p21 pathway activation** in response to DNA damage or stress signals, leading to cell cycle arrest if necessary.

Clinical Significance

Abnormalities in the G1/S transition can lead to uncontrolled cell proliferation and cancer. For example, mutations in the Rb gene, leading to a loss of Rb function, can remove the cell cycle brake, allowing for continuous cell division. Similarly, mutations in p53, one of the most common mutations in cancer, can prevent the cell from arresting the cell cycle in response to DNA damage, leading to the accumulation of mutations and cancer progression.

See Also

• Cell cycle
• DNA replication
• Cyclin-dependent kinase
• Cancer