Unit 5: Cell Cycle Control Study Notes

SLO 18: Describe the mechanisms by which cells are able to progress from one specific stage of the cell cycle to the subsequent stage.
SLO 19: Describe the fundamental importance of cell cycle control mechanisms and the role of checkpoints.
SLO 20: Discuss the specific roles of proto-oncogenes and tumor suppressor proteins at various cell cycle checkpoints.
SLO 21: Predict the physiological and cellular consequences resulting from non-functional tumor suppressor proteins or overly active oncoproteins.

Definition and Function: Specific proteins act as control mechanisms to determine whether a cell will move through a checkpoint to the next phase of the cycle.
Primary Checkpoints: * G1 Checkpoint: Occurs at the transition from the first gap phase to the S phase. * G2 Checkpoint: Occurs at the transition from the second gap phase to the M phase. * M-phase Checkpoint: Occurs during mitosis.

Significance: Referred to as the "master" checkpoint because once a cell passes this point, it is typically fated to divide.
Requirements for Progression: The cell must receive specific information to proceed, often in the form of a social signal (e.g., growth factors).
Possible Pathways at G1: * Proceed to S phase: The cell continues the cycle and begins DNA replication. * Pause: The cell halts momentarily before deciding the next step. * Withdraw to $G_0$ : When cells do not pass the checkpoint but remain in G1 for extended periods, they enter a non-dividing state known as $G_0$ . * Terminal Differentiation: When cells no longer possess the capacity to pass the G1 checkpoint because they have disassembled the necessary molecular machinery, they withdraw permanently and terminally differentiate.

Proto-oncoproteins: * Function: Actively promote the cell cycle. * Examples: Cyclins, cyclin-dependent kinases (Cdk), and E2F. * Activation: These proteins are activated by social signals.
Tumor Suppressor Proteins: * Function: Halt the cell cycle to prevent unregulated division. * Activation: These are activated by cellular stress and evidence of DNA damage.

Mechanism of MPF: * The formula for MPF is: $\text{Cyclin} + \text{Cdk} = \text{MPF}$ . * Social signals, such as growth factors, lead to the production of specific proteins like cyclin. * The accumulation of cyclin and its binding to Cdk results in active MPF. * Outcome: Active MPF promotes the cell cycle and leads to the activation of S-phase proteins.

Activation Conditions: These proteins are activated in response to DNA damage and various forms of cellular stress during both G1 and G2 phases.
Biological Responses: * Halt the cell cycle immediately. * Activate specialized DNA repair proteins. * Initiate apoptosis (programmed cell death) if the DNA damage is too extensive to repair.
Master Regulator: p53 is identified as a "master" tumor suppressor protein.

G2 Checkpoint Passing Requirements: * Chromosomes must have been replicated successfully. * The DNA must be entirely undamaged. * Activated MPF must be present in the cell.
M-phase Checkpoint Passing Requirements: * 1. Chromosomes must be properly attached to the spindle apparatus. * 2. Chromosomes must have properly segregated to opposite poles. * 3. MPF must be absent for the cell to complete the transition.

Mutations: Key cell cycle control proteins can be affected by mutations that are either inherited or acquired.
Oncogenes: When proto-oncogenes undergo mutation, they become oncogenes. This leads to the production of oncoproteins, resulting in hyper-active or over-active cell division.
Tumor Suppressor Failure: Mutated tumor suppressor genes result in inactive proteins, leading to an inability to stop cell division even when DNA damage is present.
Sources of Mutation: * Most mutations occur during the process of DNA replication. * Mutagens: Substances that directly damage DNA. * Carcinogens: Potent mutagens that specifically affect cell cycle control genes due to a high volume of accumulated mutations. * UV Light: A specific mutagen that causes the formation of thymine dimers.

Specific Oncogenes and Associated Risks: * HER2: Associated with an excessive number of copies in ovarian and breast tumors. * Ras: Linked to more than $30\%$ of all clinical tumors. * ABL: Associated with a specific type of leukemia. * Risk Escalation: High levels of cell division necessitate high levels of DNA replication, which creates an increased risk for developing additional, secondary mutations.
Specific Tumor Suppressor Losses: * Loss of p53: Linked to more than $50\%$ of all diagnosed cancers. * Loss of RB1: Linked to breast and prostate cancers. * Loss of BRCA 1 or BRCA 2: Closely linked to breast and ovarian cancers. * Loss of APC: Linked to colorectal and liver cancer.

Benign Tumors: * Characterized as localized. * Contain relatively few mutations. * Growth rate is relatively slow. * Cells continue to behave like the original cell type.
Malignant Tumors (Cancer): * Cells have the ability to migrate, a process known as metastasis. * Contain many mutations. * Growth rate is often very fast. * Cells do not behave normally.
Correlation: Malignant tumors are typically associated with both the loss of tumor suppressor proteins and the presence of oncoproteins.

Telomerase Activation: Cancer cells activate telomerase, allowing them to undergo cell division indefinitely (cellular immortality).
Growth Factor Loops: Cells release growth factors in a self-feeding loop to stimulate their own proliferation.
Angiogenesis: Cells release signals to encourage nearby blood vessels to grow toward the tumor to "feed" the malignant cells.

General Chemotherapy: Works by inhibiting the essential components of DNA replication or the physical process of cell division.
Targeted Chemotherapy: Specifically designed to inhibit the functions of specific oncogenes.
Radiation: Induces major, localized DNA damage intended to trigger programmed cell death.
Surgery: The physical removal of the primary tumor mass.
Immunotherapy: The manipulation of the patient's own immune cells to recognize and attack cancer cells.

Predicting Functional Consequences: * Question: What do you predict to be the consequence of inactive proto-oncoproteins? * Answer: (Implied) Decreased or inhibited cell division, as these proteins are required to promote the cycle. * Question: What do you predict to be the consequence of overactive proto-oncoproteins? * Answer: Unregulated, rapid cell division (oncogenesis). * Question: What do you predict to be the consequence of inactive tumor suppressor proteins? * Answer: Inability to stop division despite DNA damage, leading to the accumulation of mutations and potential malignancy. * Question: What do you predict to be the consequence of overactive tumor suppressor proteins? * Answer: (Implied) Excessive halting of the cell cycle or inappropriate apoptosis, preventing normal growth and tissue repair.