11/22 APOPTOSIS AND P53 NOTES

Announcements

• Lab Due Date: All students must submit their cancer lab analysis by Sunday.

• Upcoming Exam: 6th Exam scheduled for Monday (25th).

• Final Exam: Scheduled for Friday (13th) from 8:30 to 10:30 AM in the same room.

Focus of Today's Lecture

• Topic: Role of Apoptosis as a normal cellular process related to cancer.

• Apoptosis Definition: Programmed cell death occurring when cells detect unrepairable DNA damage at G1 to S and G2 to M checkpoints.

Importance of Apoptosis

• Multicellular Advantage: Prevents the propagation of damaged DNA by ensuring that damaged cells self-destruct.

• Cancer Development: Cancer cells arise from normal cells through the acquisition of random mutations. It typically requires 50 to 70 mutations for a cell to become fully cancerous.

• Escape from Apoptosis: Cancer cells often bypass the apoptotic process, allowing them to proliferate and spread, thereby accumulating further mutations rapidly.

Cell Cycle and Checkpoints

• Cell Cycle Regulation: Critical checkpoints (G1 to S, G2 to M) inspect for DNA damage to stop the cycle and trigger apoptosis if necessary.

• Caspases: Enzymes named caspases orchestrate the apoptosis process:

  • Initiator Caspases: Activated by specific signals, start the apoptotic cascade.

  • Executioner Caspases: Activated by initiator caspases to dismantle cellular components.

Apoptosis Pathways

1. Extrinsic Pathway

• Mechanism: Involves signals from outside the cell, particularly from the immune system.

• Death Ligands: Immune cells release signals that bind to death receptors on infected or cancerous cells, initiating apoptosis.

2. Intrinsic Pathway

• Mechanism: Triggered by internal signals, such as DNA damage or absence of survival factors.

• Role of Mitochondria:

  • Cytochrome c Release: Upon apoptotic signals, mitochondrial proteins (BAX and BAK) form channels in the outer membrane, allowing cytochrome c to leak into the cytoplasm.

  • Apoptosome Formation: Cytochrome c activates adapter proteins, forming the apoptosome, which then activates initiator caspases leading to apoptosis.

Role of BCL-2 Protein

• Function: Prevents apoptosis by sequestering BAX and BAK proteins and maintaining mitochondrial integrity.

• Trigger for Apoptosis: Lack of survival signals inhibits BCL-2, enabling the activation of BAX and BAK, leading to cytochrome c release and apoptosis.

DNA Damage and p53 Protein

• Importance of p53: Often referred to as the "guardian of the genome," p53 initiates the cellular response to DNA damage by:

  • Transcribing p21: A CDK inhibitor that halts cell cycle progression at G1 to S checkpoint to allow for DNA repair.

  • Transcribing PUMA: If damage is beyond repair, PUMA inhibits BCL-2, pushing the cell toward apoptosis.

• Mutated p53: Inherited mutations can lead to loss of function, leading to unchecked cell cycle progression, allowing damaged DNA to be replicated.

Mutation Types Related to Cancer

Oncogenes

• Definition: Genes that promote cell cycle progression (the "gas pedal").

• Gain of Function: Mutations that keep oncogenes permanently activated can lead to uncontrolled cell division.

Tumor Suppressor Genes

• Definition: Genes that inhibit cell cycle progression (the "brakes").

• Loss of Function: Mutations impair the ability to halt the cell cycle, permitting proliferation of potentially cancerous cells.

Summary of Cancer Development

• Cancer occurs due to a series of mutations in oncogenes and tumor suppressor genes, leading to unregulated cell growth.

• Effective regulation of the cell cycle is essential for maintaining cellular health, and mutations disrupting these regulations can lead to cancer.

Conclusion

• It's vital to understand the mechanisms of apoptosis and the regulation of the cell cycle to appreciate how cancer arises and how it can potentially be prevented or treated.

Announcements

• Lab Due Date: All students must submit their cancer lab analysis by Sunday. It is crucial to thoroughly analyze the data obtained during experiments and present your findings clearly to demonstrate understanding of the concepts related to cancer biology.

• Upcoming Exam: The 6th Exam is scheduled for Monday (25th). Ensure that you review all materials covered in class thoroughly, focusing on cellular processes and their implications for cancer development.

• Final Exam: Scheduled for Friday (13th) from 8:30 to 10:30 AM in the same room. This exam will encompass all topics discussed throughout the course, including but not limited to apoptosis, cell cycle regulation, and mechanisms of cancer progression.

Focus of Today's Lecture

Topic: The Role of Apoptosis as a Normal Cellular Process Related to Cancer.

Apoptosis Definition

Apoptosis is a form of programmed cell death that occurs when cells detect unrepairable DNA damage at crucial checkpoints within the cell cycle, specifically transitioning from G1 to S phase, and from G2 to M phase. This process is vital for preventing the propagation of potentially harmful mutations that could lead to cancer.

Importance of Apoptosis

• Multicellular Advantage: Apoptosis serves as a protective mechanism by preventing the survival of cells with damaged or mutated DNA, thereby ensuring overall cellular health and stability within multicellular organisms.

• Cancer Development: Cancer cells typically emerge from normal cells through an accumulation of random mutations. Studies indicate that it usually requires between 50 to 70 mutations for a single cell to progress to a fully cancerous state, undermining the body's regulatory systems.

• Escape from Apoptosis: A hallmark of many cancer cells is their ability to evade the apoptotic process, allowing them to proliferate unchecked. This evasion contributes to the accumulation of further mutations and the malignancy of tumors.

Cell Cycle and Checkpoints

• Cell Cycle Regulation: The integrity of the cell cycle is maintained through critical checkpoints (G1 to S and G2 to M) that monitor for DNA damage or incomplete replication. If damage is detected, these checkpoints trigger apoptosis to eliminate the faulty cell and prevent its division.

• Caspases: The process of apoptosis is orchestrated by a family of enzymes known as caspases.

  • Initiator Caspases: These enzymes are activated by specific signals related to cell damage or stress, and they initiate the apoptotic cascade.

  • Executioner Caspases: Upon activation by initiator caspases, these caspases dismantle key cellular components, leading to the morphological and biochemical changes characteristic of apoptosis.

Apoptosis Pathways

1. Extrinsic Pathway

   • Mechanism: This pathway is initiated by external signals, especially those produced by immune cells in response to infected or cancerous cells. The engagement of these signals with death receptors on target cells sets off the apoptotic process.

   • Death Ligands: Immune cells release specific molecules known as death ligands that bind to receptors on the surface of infected or damaged cells, triggering apoptosis.

2. Intrinsic Pathway

   • Mechanism: This pathway is activated by internal cellular stressors, including significant DNA damage or the absence of essential survival signals.

   • Role of Mitochondria:

     • Cytochrome c Release: Critical mitochondrial proteins, specifically BAX and BAK, form channels in the mitochondrial outer membrane upon receiving apoptotic signals. This process allows cytochrome c to escape into the cytoplasm.

     • Apoptosome Formation: Once in the cytoplasm, cytochrome c interacts with adapter proteins to form a complex called the apoptosome. The formation of this structure then activates initiator caspases, leading to a cascading effect that ultimately results in cell death.

Role of BCL-2 Protein

• Function: The BCL-2 family of proteins plays a significant role in regulating apoptosis. BCL-2 specifically inhibits apoptosis by sequestering pro-apoptotic proteins such as BAX and BAK, thereby maintaining mitochondrial integrity and cellular survival.

• Trigger for Apoptosis: In the absence of survival signals, the inhibition on BAX and BAK is lifted, which allows these proteins to initiate cytochrome c release and cascade into apoptosis.

DNA Damage and p53 Protein

• Importance of p53: Often referred to as the "guardian of the genome," p53 is a critical tumor suppressor protein that responds to cellular stress and DNA damage by:

  • Transcribing p21: This CDK inhibitor halts the progression of the cell cycle at the G1 to S checkpoint, allowing time for DNA repairs to occur.

  • Transcribing PUMA: In instances where the DNA damage cannot be repaired, PUMA serves to inhibit BCL-2, promoting apoptosis as the best course of action.

• Mutated p53: Inherited mutations in the p53 gene can lead to the loss of its normal function, resulting in unregulated cell cycle progression and the replication of damaged DNA, a precursor to cancer development.

Mutation Types Related to Cancer

• Oncogenes

  • Definition: Oncogenes are genes that promote cell cycle progression, effectively acting as the "gas pedal" of cell division.

  • Gain of Function: Mutations that lead to the persistent activation of oncogenes can result in uncontrolled cell division, contributing significantly to cancer development.

• Tumor Suppressor Genes

  • Definition: These genes act to inhibit cell cycle progression, functioning as the "brakes" that prevent uncontrolled cellular growth.

  • Loss of Function: Mutations that impair the function of tumor suppressor genes can negate these braking mechanisms, allowing for the potentially cancerous proliferation of cells.

Summary of Cancer Development

Cancer is the result of a gradual accumulation of mutations within oncogenes and tumor suppressor genes, which disrupt standard regulation of the cell cycle and lead to unregulated cell growth. Understanding the mechanisms of apoptosis and how the cell cycle is regulated is essential for appreciating the onset of cancer and exploring potential preventive and therapeutic strategies.

Conclusion

Grasping the complex interplay between apoptosis, cell cycle regulation, and mutation dynamics is vital for understanding cancer pathogenesis. Insights into these processes are crucial for the development of targeted treatments and interventions aimed at cancer prevention