Cell Cycle Regulation and Pathology

• Cell cycle regulation and disruption is examined, focusing on its relevance to pathology.
• Cell cycle progression is a series of ordered events essential for cell proliferation.
• The cell cycle is crucial for organism development and tissue homeostasis, which involves replacing dead or damaged cells.
• Tissue homeostasis relies on stem cells due to their regenerative properties.
• Accurate DNA replication and division of cellular components are defining characteristics of the cell cycle.
• Errors in replication or division can lead to genetic instability and diseases like cancer.

Cell Cycle Phases and Pathology

• G0 phase consists of cells that are not actively cycling, such as differentiated or specialized cells
• Permanent cells like neurons and cardiac myocytes are in G0 and have lost the capacity to proliferate.
• Myocardial infarctions and strokes have high mortality rates because of damage, and the fact that permanent cells cannot be replaced.
• Stable cells like hepatocytes are in G0 but can re-enter the cell cycle, giving the liver limited regenerative capacity.
• Labile tissues like the gastrointestinal tract and epidermis have high cell turnover and continuous division, which makes them more prone to cancers like GI and skin cancers.
• G1-S DNA damage checkpoint monitors DNA integrity before replication
• G2-M checkpoint ensures that DNA replication has completed accurately.
• Checkpoints prevent cells with damaged or unduplicated DNA from progressing through the cell cycle.
• Cancer cells often bypass these checkpoints, which allows them to proliferate uncontrollably.
• Oncology research focuses on developing drugs to reactivate checkpoints in cancer cells.
• Cancer cells can develop resistance to therapies through immune mechanisms.

Regulation of the Cell Cycle

• Cell cycle regulation involves a balance between activators and inhibitors.
• Activators are cyclin-CDK complexes, which phosphorylate substrates to promote cell cycle progression.
• Cyclins are proteins that fluctuate in cyclical patterns, and Cyclin-dependent kinases (CDKs) are enzymes activated by cyclins.
• Key cyclins include Cyclins A, B, D, and E.
• Cyclin synthesis increases as the cell progresses through different stages with resultant CDK activation.
• After the cell cycle is complete, cyclins degrade leading to reduced CDK activity.

Phase Transitions

• G1-S transition requires passing the G1 restriction point, which ensures DNA integrity.
• Transition is regulated by phosphorylation of retinoblastoma protein (Rb) controlled by Cyclin D-CDK4/6 and Cyclin A-CDK2 complexes.
• DNA replication happens during the S phase
• The G2-M restriction point ensures that DNA replication is completed and accurate before mitosis begins.
• Defective DNA triggers DNA repair or delays division, regulated by Cyclin B-CDK1 complexes.
• Severe DNA damage induces senescence (growth arrest) via p53-dependent mechanisms or apoptosis (programmed cell death).

Inhibitors of the Cell Cycle

• Cyclin-dependent kinase inhibitors (CKIs) inhibit cyclin-CDK complexes to halt cell cycle progression.
• Broad-spectrum inhibitors like p21, p27, and p57 inhibit multiple cyclin-CDK complexes.
• Specific inhibitors like p15, p16, p18, and p19 primarily act on CDK4 and CDK6 to prevent Rb phosphorylation and halt cell cycle progression.

Cancer Therapies

• Understanding cell cycle mechanisms is critical for developing targeted cancer therapies.
• Targeting cyclins, CDKs, and checkpoints provides insights into regulating cell division and treating cancer.

Additional Information

• p53 initiates cell cycle arrest, senescence, or apoptosis in response to DNA damage, so inhibiting p53 would allow proliferation of cells with damaged DNA.
• Cyclin degradation is crucial for proper timing and progression of the cell cycle.
• If cyclins are unable to be degraded, it leads to unregulated growth, which causes the cell cycle to proceed without proper regulation Inhibiting CDK4 and CDK6 prevents phosphorylation of Rb to halt the cell cycle in the G1 phase, thus preventing cancer cells from dividing.
• Cancer cells often develop mutations to disable or bypass cell cycle checkpoints.
• Elevated Cyclin D levels means progression through the G1-S phase increases, indicating increased cell proliferation, common in cancerous growth.

Answers to Questions

• Question 2: D is the correct answer, cells with damaged DNA can bypass checkpoints, and continue dividing, if p53 is inhibited.
• Question 3: A is correct. If the cell's ability to degrade cyclins is disabled, the cell cycle would progress uncontrollably, bypassing normal regulatory checkpoints
• Question 5: B is the correct answer, the intended outcome of a new drug that specifically targets and inhibits CDK4 and CDK6 is to prevent phosphorylation of Rb protein, halting the cell cycle in G1.
• Question 7: A is the correct answer as cancer cells overcome the normal cell cycle checkpoints by developing mutations that disable or bypass checkpoint controls.
• Question 9: B is the answer as cells are rapidly progressing through G1-S restriction point when researchers observe unusually high levels of Cyclin D in a tissue sample from a patient with an aggressive form of cancer.