negative regulation of cell cycle G1/S phase transition

Definition

Target type: biologicalprocess

Any signaling pathway that decreases or inhibits 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]

Negative regulation of cell cycle G1/S phase transition is a crucial process that prevents uncontrolled cell division and ensures proper cellular growth and development. It involves a complex interplay of proteins and signaling pathways that act to inhibit the transition from the G1 phase, a period of growth and preparation, to the S phase, where DNA replication occurs. This regulation is essential for maintaining genomic stability, preventing uncontrolled proliferation, and ensuring that cells only divide when appropriate.

Here's a detailed description of the biological process:

1. **Cyclin-Dependent Kinases (CDKs) and Cyclins:** CDKs are key enzymes that drive the cell cycle, and their activity is regulated by cyclins, which are proteins that bind to CDKs and activate them. For the G1/S transition, CDK4 and CDK6 are crucial, along with their respective cyclin partners, cyclin D1, D2, and D3.

2. **Retinoblastoma Protein (Rb):** Rb is a tumor suppressor protein that acts as a brake on the cell cycle. In its active, hypophosphorylated state, Rb binds to transcription factors, such as E2F, preventing them from activating genes required for S phase entry.

3. **Growth Factor Signaling:** Growth factors, such as epidermal growth factor (EGF), stimulate cell growth and proliferation. They activate signaling pathways, like the mitogen-activated protein kinase (MAPK) pathway, which ultimately lead to the phosphorylation of Rb by CDK4/6-cyclin D complexes.

4. **Phosphorylation of Rb:** Phosphorylation of Rb by CDK4/6-cyclin D complexes causes a conformational change in Rb, leading to its dissociation from E2F. This frees E2F to activate the transcription of genes required for S phase entry, including those involved in DNA replication, nucleotide synthesis, and centrosome duplication.

5. **G1/S Checkpoint:** This checkpoint ensures that the cell is ready to proceed into S phase. It involves the activity of other CDKs, like CDK2, which, in conjunction with cyclin E, further phosphorylates Rb, solidifying its inactivation. Additionally, the checkpoint monitors DNA damage and ensures that any damage is repaired before replication.

6. **Negative Regulation:** Negative regulation of the G1/S transition is crucial for maintaining cell cycle control. This is achieved through various mechanisms:

a. **Cyclin-Dependent Kinase Inhibitors (CKIs):** These proteins, such as p21 and p27, bind to and inhibit CDKs, blocking their activity and preventing Rb phosphorylation.

b. **DNA Damage Response:** If DNA damage is detected, signaling pathways are activated that lead to the production of CKIs, halting the cell cycle at the G1/S checkpoint and allowing time for DNA repair.

c. **Tumor Suppressor Genes:** Genes like p53, a key player in DNA damage response, can induce cell cycle arrest or apoptosis (programmed cell death) if DNA damage is too severe.

7. **Dysregulation and Cancer:** Dysregulation of the G1/S transition is a hallmark of cancer. Mutations in genes involved in this process, such as Rb, p53, or CDKs, can lead to uncontrolled cell proliferation and tumor formation.

In summary, negative regulation of the cell cycle G1/S phase transition is a complex and tightly regulated process that ensures proper cell growth, genomic stability, and prevents uncontrolled proliferation. It involves a delicate balance of signaling pathways, proteins, and checkpoints that ensure cells only divide when appropriate and prevent uncontrolled growth that could lead to cancer.'
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Proteins (2)

Compounds (4)