BIOL112 lecture12 EDI_9f89d3db6ce3f204673dff9270fdc8ba

Overview of Cell Reproduction and Tumour Suppressor Genes

Lecture 9: Description of the cell cycle and the role of cellular structures (e.g., mitotic spindle) in mitosis.
Lecture 10: Regulation of the cell cycle involving checkpoints and roles of SPF, MPF, APC in cell cycle progression.
Lecture 11: Introduction to cancer, including facts, disease progression, and oncogenes (e.g., Ras).
Lecture 12: Second class of cancer-causing genes focusing on tumour suppressor genes (e.g., Retinoblastoma, p53).

Define tumour suppressor genes.
Provide examples of tumour suppressor genes.
Explain how mutations in these genes lead to cancer.
Describe the roles of the p53 protein in the cell cycle and its association with cancer.
Define apoptosis and how it acts to protect against cancer.

Function: Tumour suppressor genes traditionally inhibit cell division, acting as a safeguard against excessive cell proliferation.
Mutations: Mutations can reduce the inhibitory effects of these genes, thereby leading to increased unchecked cell replication and potential tumor formation.
Recessive Effects: Only one functional copy of a tumour suppressor gene is needed for normal function; however, both copies must be mutated to cause cancer, which is known as recessive inheritance.

Diploid Cells: In normal diploid cells, there are two copies of each chromosome, making the mutation of both copies necessary for cancer development (recessive pattern).
Proto-oncogene Mutations: Proto-oncogenes, when mutated, can become oncogenes that activate dominant proteins (e.g., Ras), contributing to uncontrolled cell growth and division.

Tumour Characteristics: Retinoblastoma is a type of cancer that occurs in the retina with two forms:
- Familial (10%): Usually manifests in young children and often affects both eyes, due to inherited mutations.
- Sporadic (90%): More common in older individuals and typically involves one eye (2/3 of cases).
Early Sign: Leukocoria (white reflex) is often the first sign signaling potential retinoblastoma.
Cellular Recessiveness: The disease is considered recessive at the cellular level; both copies of the Rb gene must be mutated to result in cancer.

A child inherits one normal and one mutant Rb gene. With both copies mutated, the protective function against tumor formation is lost, prompting cancer.
The high frequency of retinoblastoma indicates a significant presence of both inherited and somatic mutations impacting tumor risk.

Role: The Rb protein inhibits the cell cycle by controlling the transition from G1 to S phase, preventing cells from duplicating uncontrollably.
Consequences of Mutation: Mutational inactivation of Rb leads to a loss of this critical checkpoint control, resulting in unregulated cell division and tumor growth.

General Information: p53 is a vital tumor suppressor protein, approximately 53 kDa in size, commonly mutated across various cancers.
Main Role: It functions primarily to protect cells from DNA damage, halting the cell cycle to provide time for repair prior to mitosis.
Mechanism of Action: As a transcription factor, p53 regulates genes involved in DNA repair, cell cycle arrest, and apoptosis, playing a pivotal role in maintaining genetic fidelity.

DNA Damage Recognition: p53 recognizes damaged DNA and proactively activates repair mechanisms.
If Damage Is Irreparable: Should the damage be deemed catastrophic, p53 will trigger cellular senescence or apoptosis, preventing the propagation of damaged cells.

Activation Cascade: DNA damage results in phosphorylation cascades that will effectively stabilize and activate p53.
Transcriptional Activation: Stabilized p53 acts as a transcription factor, initiating the expression of genes that halt the cell cycle, thus preventing the division of cells with damaged DNA.

Mechanism Defined: Apoptosis, or programmed cell death, is a protective process that eliminates dangerous cells without causing inflammation or harm to surrounding tissues.
Intrinsic Pathway: p53 initiates apoptosis through the intrinsic pathway by activating Bid, which leads to mitochondrial changes prompting the release of cytochrome c. This then activates caspases, the executioners of apoptosis.
Extrinsic Pathway: This pathway involves the activation of death receptors on the cell surface and the assembly of a death-inducing signaling complex (DISC), leading to apoptotic signaling pathways.

p53 is essential for DNA repair, regulating the cell cycle, and controlling apoptosis, all of which maintain genomic integrity and stability.
Mutation Consequences: Mutations that inactivate p53 can result in significant tumorigenesis as it allows damaged cells to avoid detection and survival, leading to uncontrolled proliferation and eventual cancer development.

Cancer progression typically involves a series of genetic mutations that transition from benign polyps to malignant tumors.
Loss of heterozygosity in tumour suppressor genes is a critical step in cancer development, demonstrating the need for multiple genetic changes for full tumor malignancy.

Define tumour suppressor genes and their mechanisms.
Describe how p53 contributes to genomic stability and regulates cell cycle, apoptosis, and DNA repair.