cell cycle regulation

Definition: Cyclins are proteins that are synthesized and degraded in a cyclical manner during the cell cycle.
Function: Their levels rise and fall, coordinating with different phases of the cell cycle, which is why they are termed "cyclins."

Definition: CDKs are cyclin-dependent kinases that phosphorylate target proteins essential for cell cycle progression.
Dependency: They require binding to cyclins to be active, functioning together as a unit to regulate the cell cycle.
Type: CDKs are serine/threonine kinases, specifically phosphorylating serine and threonine residues

CDKs act on several target proteins and their activity is regulated by various kinases and phosphatases.
Key Cyclin-CDK Complexes:
- G1 Phase: Cyclin D with CDK4/6
- S Phase: Cyclin E with CDK2
- End of S Phase: Cyclin A with CDK2
- M Phase: Cyclin B with CDK1.

Activation: Triggered by growth factor signaling. Cyclin D is produced in response to mitogenic signaling, indicating adequate growth factor presence.
MAPK Pathway: Cyclin D is a significant downstream target of the RAS-RAF-MAPK pathway, tied to cell growth signals.
Restriction Point Decision: Cyclin D and CDK4 regulate whether a cell should proceed to division based on nutrient availability and stress factors. Crossing this point means the cell commits to division.
Role of pRB: The retinoblastoma protein (pRB) acts as a tumor suppressor, controlling E2F (a crucial transcription factor).
- E2F can bind to DNA for transcription, leading to production of cyclins necessary for the S phase, progressing the cell cycle.
- pRB binds to E2F and inhibits its activity.
- CDK4/cyclin D phosphorylates pRB, freeing E2F to transcribe genes necessary for S phase entry, such as cyclin E. This allows the cell cycle to progress from the G phase to the S phase.

Function: p53 is another tumor suppressor responsible for cell cycle regulation and apoptosis.
- p53 is able to pause the cell cycle.
Response to DNA Damage:
- Damage in G1 prompts activation of p53 via DNA damage sensors (ATM, ATR) and signaling pathways (e.g., CHK2).
- Activated p53 can induce expression of p21, which inhibits cyclin-CDK activity, pausing the cell cycle to allow for DNA repair or causing the cell to undergo apoptosis if damage is irreparable.
  - Pausing the cell cycle gives DNA repair machinery time to repair the damage. Once the damage is repaired, the cell cycle is able to continue again.
  - If damage is beyond repair, apoptosis is triggered.

Cyclin E and CDK2 are essential for initiating DNA replication.
Replication Licensing: At the end of G1, preparation for replication involves CDT1 and CDC6 binding to the origin of replication complex.
Phosphorylation: Cyclin E-CDK2 complex phosphorylates CDT1 and CDC6, permitting the formation of the replication bubble.
Purpose: This phosphorylation ensures replication occurs only once per cell cycle.

Phosphorylation Sites: Threonine 14 and 15 (inhibitory) and Threonine 161 (activatory).
Activation Process: Inhibitory sites are regulated by kinases (WEEl) and activating phosphatases (CDC25).
Functions: Critical for chromosome condensation, nuclear envelope breakdown, Golgi fragmentation, and spindle apparatus formation.
Degradation: Post M phase, cyclin B is targeted for ubiquitination by the anaphase-promoting complex for degradation.
Role in Chromosome Packaging: Cyclin B-CDK1 phosphorylates lamins, enabling nuclear envelope breakdown and chromosome condensation necessary for mitosis.

Cyclins and CDKs play integral roles in regulating the cell cycle phases (G1, S, and M) through intricate signaling pathways and interactions with tumor suppressors like pRB and p53. Understanding these interactions is vital for insights into cell cycle control and cancer biology.