Cancer and Cell Cycle Checkpoints

The cell cycle is the series of events that take place in a cell leading to its division and replication. The
cell cycle is tightly regulated by a series of checkpoints that ensure cells only divide when conditions are
appropriate. These checkpoints act as surveillance mechanisms to prevent damaged or abnormal cells
from dividing.

Cell Cycle Checkpoints and Their Role

 G1 Checkpoint (Restriction Point): The cell checks for DNA damage and whether it has the
nutrients and signals needed for division. If conditions are not favorable or DNA is damaged, the
cell can enter a resting phase (G0) or trigger DNA repair mechanisms.

 G2 Checkpoint: This checkpoint ensures that the DNA has been fully replicated without errors. It
checks for DNA damage or incomplete DNA replication. If there are errors, the cell cycle is halted
to allow for repair.

 M Checkpoint (Spindle Checkpoint): Occurs during mitosis and ensures that chromosomes are
properly aligned on the metaphase plate before division. If the chromosomes are not aligned
correctly, the cell will halt mitosis to prevent uneven distribution of genetic material.

If these checkpoints fail due to mutations in the genes that control them, cells with damaged DNA can
proceed through the cell cycle and divide uncontrollably, leading to the formation of tumors. Cancer
often arises from the failure of these critical regulatory mechanisms.

Oncogenes and Proto-oncogenes

Proto-oncogenes

Proto-oncogenes are normal genes that encode proteins involved in cell growth, differentiation, and
survival. These proteins often function in signal transduction pathways and the regulation of the cell
cycle. When functioning properly, proto-oncogenes help promote normal cell division and
differentiation.

Function: Proto-oncogenes are involved in processes such as:

Regulation of the cell cycle (e.g., cyclins and cyclin-dependent kinases)

Signal transduction (e.g., growth factors and their receptors like EGFR)

Cell survival (e.g., anti-apoptotic proteins)

Cell differentiation (e.g., transcription factors)

Ras: A small GTPase involved in cell signaling, regulating processes like cell proliferation. Mutations in
Ras can lead to continuous activation of the signaling pathway, causing uncontrolled cell division.

Myc: A transcription factor involved in the regulation of genes that promote cell growth and division.
Overexpression of Myc can lead to increased cell proliferation and tumor formation.

HER2 (Human Epidermal Growth Factor Receptor 2): A receptor tyrosine kinase involved in the
regulation of cell growth. Overexpression of HER2 is implicated in some types of breast cancer.

Oncogenes

Oncogenes are mutated or overexpressed versions of proto-oncogenes. These mutations can result in
proteins that are hyperactive or overproduced, driving abnormal cell growth and contributing to cancer.

Activation of Oncogenes:

Point mutations: A single nucleotide change can lead to a protein that is always active (e.g., Ras
mutation).

Gene amplification: An increase in the number of copies of a gene can lead to overproduction of the
encoded protein (e.g., HER2 amplification in breast cancer).

Chromosomal translocation: A part of a chromosome may break off and attach to another
chromosome, leading to the production of a fusion gene that encodes a protein with abnormal function
(e.g., BCR-ABL fusion gene in chronic myelogenous leukemia).

Examples of Oncogenes:

Ras (mutated): A mutated Ras protein can constantly signal the cell to proliferate, even in the absence
of external growth signals.

BCR-ABL: A fusion gene resulting from a translocation between chromosomes 9 and 22, commonly
found in chronic myelogenous leukemia (CML). This fusion gene leads to uncontrolled cell growth.

Cyclin D1: Cyclin D1 regulates the cell cycle's transition from G1 to S phase. Overexpression of Cyclin D1
is associated with many cancers, including breast cancer.

Tumor Suppressor Genes

Tumor suppressor genes are genes that normally regulate the cell cycle, promote DNA repair, and
induce apoptosis (programmed cell death) when necessary. These genes act as "brakes" on cell division
to prevent the development of tumors.

Function: Tumor suppressor genes play key roles in:

Inhibiting the cell cycle at checkpoints (e.g., p53 and Rb)

Inducing apoptosis in cells with damaged DNA

Regulating the interaction between cell cycle regulators (e.g., p21, p16)

Loss of Function in Tumor Suppressor Genes

 Tumor suppressor genes follow the two-hit hypothesis—both copies of the gene must be
mutated or inactivated to contribute to cancer. This is in contrast to oncogenes, where only a
single mutation can activate the gene.

 When tumor suppressor genes are inactivated, they can no longer properly regulate the cell
cycle, repair DNA, or induce apoptosis, allowing cells with damaged DNA to survive and divide
uncontrollably.

Examples of Tumor Suppressor Genes:

p53: Often called the "guardian of the genome," p53 is a key tumor suppressor gene that monitors DNA
integrity. It can halt the cell cycle in response to DNA damage and trigger apoptosis if the damage is
irreparable. Mutations in p53 are found in over 50% of human cancers.

Retinoblastoma (Rb): The Rb gene produces a protein that regulates the transition from G1 to S phase
of the cell cycle by binding and inhibiting the E2F transcription factor. Mutations in Rb are linked to
retinoblastoma and other cancers.

BRCA1 and BRCA2: These genes are involved in DNA repair, specifically the repair of double-strand
breaks. Mutations in BRCA1 and BRCA2 increase the risk of breast, ovarian, and other cancers.

APC: The APC gene helps regulate the Wnt signaling pathway, which controls cell growth. Mutations in
APC are a major cause of familial adenomatous polyposis, a hereditary condition that greatly increases
the risk of colon cancer.

Cancer: The Result of Genetic Imbalance

Oncogenes vs Tumor Suppressor Genes: Cancer can result from an imbalance between the activation of
oncogenes (which promote cell growth) and the inactivation of tumor suppressor genes (which normally
prevent uncontrolled growth).

Mechanisms Leading to Cancer:

Activation of Oncogenes: A mutated proto-oncogene becomes an oncogene, promoting cell

The Role of Cell Cycle Checkpoints: The checkpoints that regulate the cell cycle become ineffective if
tumor suppressor genes (e.g., p53, Rb) are mutated. Without proper checkpoints, damaged or mutated
cells are allowed to divide uncontrollably, leading to tumor formation and metastasis.

Cancer is a genetic disease caused by mutations in key regulatory genes that control the cell cycle and
cell survival. Oncogenes (mutated proto-oncogenes) promote uncontrolled cell growth, while tumor
suppressor genes normally act as brakes to prevent tumor formation. Cell cycle checkpoints are crucial
for detecting DNA damage and halting cell division when necessary, and their failure often results in
cancer. Understanding the interactions between these genetic elements is key to developing effective
cancer therapies, particularly those that target specific oncogenes and restore the function of tumor
suppressor genes.