PROTO ONCO GENES

ONCO GENES
TUMOUR SUPPRESSOR GENE
REGULATION OF CELL CYCLE IN MALIGNANT CELLS
PROTO ONCO GENES
Proto-oncogenes are normal genes that play a
crucial role in cell growth, division, and
differentiation. They encode proteins that help to
regulate cell processes, such as growth factors,
receptors, signaling molecules, and transcription
factors. When these genes become mutated or
abnormally activated, they can transform into
oncogenes, which may lead to uncontrolled cell
proliferation and cancer.

### Examples of Proto-oncogenes:

1. **RAS**: Encodes a family of proteins involved in
transmitting signals within cells. Mutations in RAS
genes are common in various cancers.
2. **MYC**: Encodes a transcription factor that
regulates gene expression and is involved in cell
cycle progression, apoptosis, and cellular
transformation.
3. **HER2/neu**: Encodes a receptor tyrosine
kinase that is involved in the growth and
differentiation of cells. Overexpression or
amplification of HER2 is associated with certain
types of breast cancer.
4. **SRC**: Encodes a non-receptor tyrosine kinase
that is involved in the regulation of cellular
processes, including growth and differentiation.
5. **ABL**: Encodes a non-receptor tyrosine kinase
that, when fused with the BCR gene due to
chromosomal translocation, can lead to chronic
myelogenous leukemia (CML).

### How Proto-oncogenes Become Oncogenes:

1. **Mutation**: Changes in the DNA sequence of a
proto-oncogene can lead to a protein that is
constantly active or overactive.
2. **Gene Amplification**: An increase in the
number of copies of a proto-oncogene can lead to
excessive amounts of the protein.
3. **Chromosomal Translocations**: Parts of
chromosomes can break and reattach to different
chromosomes, leading to the creation of a new gene
that is overactive or always active.
4. **Viral Integration**: Some viruses can insert
their genetic material near proto-oncogenes, leading
to their abnormal activation.

Understanding proto-oncogenes and their role in

cancer can help in the development of targeted
therapies and diagnostic tools for various types of
cancer.
ONCO GENES
Oncogenes are mutated or abnormally activated
versions of proto-oncogenes. When a proto-
oncogene is altered in a way that leads to its
constant activation or overexpression, it can drive
the uncontrolled cell proliferation that is
characteristic of cancer. Unlike tumor suppressor
genes, which require both alleles to be inactivated to
contribute to cancer, a single altered allele of a
proto-oncogene can be sufficient to drive the
cancerous transformation.

### Mechanisms of Oncogene Activation:

1. **Point Mutations**: Single nucleotide changes in
the DNA sequence can create a hyperactive version
of the protein.
2. **Gene Amplification**: Multiple copies of the
gene lead to overproduction of the encoded protein.
3. **Chromosomal Translocations**: Reorganization
of chromosomal material can create fusion genes
that encode for proteins with enhanced or new
oncogenic properties.
4. **Viral Insertion**: Viruses can integrate their
genetic material into the host genome near proto-
oncogenes, leading to their activation.

### Examples of Oncogenes:

1. **RAS**: Mutations in RAS genes (such as KRAS,
HRAS, and NRAS) are common in many cancers,
including pancreatic, colorectal, and lung cancers.
Mutant RAS proteins are constantly active,
promoting uncontrolled cell growth.
2. **MYC**: Overexpression or amplification of MYC
is found in various cancers, including Burkitt's
lymphoma and breast cancer. MYC regulates the
expression of many genes involved in cell cycle
progression and apoptosis.
3. **BCR-ABL**: Resulting from a chromosomal
translocation between chromosomes 9 and 22, this
fusion gene is found in chronic myelogenous
leukemia (CML). The BCR-ABL protein has constant
tyrosine kinase activity, leading to uncontrolled cell
division.
4. **HER2/neu (ERBB2)**: Amplification or
overexpression of HER2 is found in some breast
cancers and is associated with aggressive disease.
HER2 is a receptor tyrosine kinase involved in cell
growth and differentiation.
5. **SRC**: Originally identified in a chicken virus,
the SRC oncogene encodes a tyrosine kinase that,
when mutated, can lead to various human cancers.

### Therapeutic Implications:

Targeting oncogenes with specific therapies can be
an effective strategy in cancer treatment. Examples
include:
- **Tyrosine Kinase Inhibitors (TKIs)**: Drugs like
imatinib (Gleevec) target the BCR-ABL fusion protein
in CML.
- **Monoclonal Antibodies**: Drugs like
trastuzumab (Herceptin) target HER2-positive breast
cancers.
- **RAS Pathway Inhibitors**: Targeting downstream
components of the RAS signaling pathway can be
effective in treating cancers with RAS mutations.

Understanding the mechanisms of oncogene

activation and their role in cancer progression is
crucial for developing targeted therapies and
improving cancer treatment outcomes.
TUMOUR SUPPRESSOR GENE
Tumor suppressor genes are genes that help
regulate cell growth and division, repair DNA
damage, and ensure that cells undergo apoptosis
(programmed cell death) when necessary. When
these genes are inactivated or lost through
mutations, deletions, or other genetic alterations,
cells can grow uncontrollably, leading to the
development of cancer. Unlike oncogenes, which can
promote cancer with a single mutated allele, both
copies of a tumor suppressor gene usually need to
be inactivated for cancer to develop.

### Functions of Tumor Suppressor Genes:

1. **Regulation of Cell Cycle**: Ensure cells do not
divide uncontrollably.
2. **DNA Repair**: Fix mutations or damage in the
DNA.
3. **Apoptosis**: Trigger cell death when damage is
irreparable.
4. **Cell Adhesion**: Maintain tissue architecture
and prevent metastasis.

### Examples of Tumor Suppressor Genes:

1. **TP53**: Encodes the p53 protein, which plays a
critical role in controlling cell division and apoptosis.
Mutations in TP53 are found in over half of all
human cancers.
2. **RB1**: Encodes the retinoblastoma protein
(pRB), which regulates the cell cycle by controlling
the transition from the G1 phase to the S phase.
Mutations in RB1 can lead to retinoblastoma and
other cancers.
3. **BRCA1 and BRCA2**: Involved in DNA repair
through homologous recombination. Mutations in
these genes significantly increase the risk of breast
and ovarian cancers.
4. **APC**: Encodes a protein that helps regulate
cell division and adhesion. Mutations in APC are
associated with familial adenomatous polyposis
(FAP) and colorectal cancer.
5. **PTEN**: Encodes a phosphatase that negatively
regulates the PI3K/AKT signaling pathway, which is
involved in cell growth and survival. PTEN mutations
are implicated in various cancers, including prostate,
breast, and endometrial cancers.

### Mechanisms of Tumor Suppressor Gene

Inactivation:
1. **Point Mutations**: Changes in the DNA
sequence can lead to a non-functional protein.
2. **Deletions**: Loss of a segment of a
chromosome that includes the tumor suppressor
gene.
3. **Epigenetic Changes**: Methylation of DNA can
silence gene expression without changing the DNA
sequence.
4. **Loss of Heterozygosity (LOH)**: The second,
normal allele of a gene is lost or inactivated in a cell
that already has one mutated allele.

### Therapeutic Implications:

Understanding tumor suppressor genes and their
pathways has led to the development of targeted
therapies and strategies to restore their function.
For example:
- **PARP Inhibitors**: Used in cancers with BRCA1
or BRCA2 mutations by exploiting synthetic lethality.
- **Checkpoint Inhibitors**: Target immune
checkpoints to enhance the immune system's ability
to recognize and destroy cancer cells with
dysfunctional p53.

Research into tumor suppressor genes continues to

be crucial for developing novel cancer treatments
and improving patient outcomes.
REGULATION OF CELL CYCLE IN MALIGNANT CELL

In malignant cells, the regulation of the cell cycle is

often disrupted, leading to uncontrolled
proliferation. Normal cells tightly control the cell
cycle through a series of checkpoints and regulatory
proteins that ensure DNA is accurately replicated
and any damage is repaired before the cell divides.
In cancer cells, mutations and alterations in these
regulatory mechanisms allow cells to bypass these
controls, leading to rapid and unchecked growth.

### Key Components of Cell Cycle Regulation:

1. **Cyclins and Cyclin-Dependent Kinases (CDKs)**:

- Cyclins are regulatory proteins that control the
progression of cells through the cell cycle by
activating CDKs.
- Different cyclins are produced at different stages
of the cell cycle (e.g., Cyclin D in G1 phase, Cyclin E
in S phase).
- CDKs, once activated by binding to cyclins,
phosphorylate target proteins to drive the cell cycle
forward.

2. **CDK Inhibitors (CKIs)**:

 - Proteins such as p21, p27, and p16 inhibit the
activity of cyclin-CDK complexes, acting as brakes on
the cell cycle.
- In malignant cells, these inhibitors are often
inactivated or downregulated, removing the brakes
on cell proliferation.

3. **Tumor Suppressor Proteins**:

- **p53**: Responds to DNA damage by inducing
cell cycle arrest, DNA repair, or apoptosis. Mutations
in TP53 are common in many cancers, leading to loss
of these protective mechanisms.
- **RB (Retinoblastoma protein)**: Controls the
G1 to S phase transition by inhibiting E2F
transcription factors. When RB is phosphorylated,
E2F is released, allowing the cell cycle to progress.
Mutations in RB1 can lead to uncontrolled cell
division.

4. **Cell Cycle Checkpoints**:

- **G1/S Checkpoint**: Ensures that the cell is
ready for DNA synthesis. p53 and RB play critical
roles here.
- **G2/M Checkpoint**: Ensures that DNA
replication is complete and that any damage is
repaired before mitosis.
 - **Spindle Assembly Checkpoint**: Ensures that
all chromosomes are properly attached to the
spindle fibers before the cell divides.

### Dysregulation in Malignant Cells:

1. **Overexpression of Cyclins**: Many cancers

have elevated levels of cyclins, leading to increased
CDK activity and rapid cell cycle progression.
- For example, Cyclin D1 is often overexpressed in
breast cancer.
2. **Mutations in CDKs and CKIs**: Mutations that
lead to constant activation of CDKs or inactivation of
CKIs can drive cancer progression.
- For example, mutations in CDK4 that make it
resistant to inhibition by p16INK4a.

3. **Loss of Tumor Suppressors**: Mutations or

deletions in tumor suppressor genes like TP53 and
RB1 remove critical checkpoints.
- The loss of p53 function leads to the inability to
arrest the cell cycle in response to DNA damage.
- The inactivation of RB leads to uncontrolled E2F
activity and cell cycle progression.
4. **Activation of Oncogenes**: Oncogenes such as
MYC can drive the expression of cyclins and other
proteins that promote cell cycle progression.
- MYC overexpression leads to increased
transcription of genes necessary for cell cycle
progression.

### Therapeutic Implications:

Understanding the dysregulation of the cell cycle in
malignant cells has led to the development of
targeted therapies:
- **CDK Inhibitors**: Drugs like palbociclib (Ibrance)
inhibit CDK4/6, which are critical for the G1 to S
phase transition, and are used in the treatment of
certain types of breast cancer.
- **Checkpoint Inhibitors**: Enhancing the immune
response against tumor cells that evade the immune
system by exploiting checkpoint pathways.
- **PARP Inhibitors**: Targeting DNA repair
pathways in cancers with defective p53 or BRCA
mutations, exploiting synthetic lethality.

Therapies targeting cell cycle dysregulation hold

promise in improving cancer treatment outcomes by
specifically addressing the mechanisms that allow
cancer cells to proliferate uncontrollably.