An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated or expressed at high levels. Most normal cells will undergo a programmed form of rapid cell death (apoptosis) when critical functions are altered and malfunctioning

1. ONCOGENE

2. • Oncogenes are mutated genes that can contribute to the development
of cancer.
• In their non-mutated state, everyone has genes which are referred to
as proto-oncogenes. When proto-oncogenes are mutated or increased
in numbers (amplification) due to DNA damage (such as exposure to
carcinogens), the proteins produced by these genes can affect the
growth, proliferation, and survival of the cell, and potentially result in
the formation of a malignant tumor.
• There are many checks and balances in place, and the development of
cancer most often requires mutations or other genetic changes in both
oncogenes and tumor suppressor genes (genes that produce proteins
that either repair or eliminate damaged cells).

4. HISTORY

5. • The concept of oncogenes had been theorized for over a century, but the
first oncogene was not isolated until 1970 when an oncogene was
discovered in a cancer-causing virus called the rous sarcoma virus (a
chicken retrovirus).
• It was well known that some viruses, and other microorganisms, can
cause cancer and in fact, 20% to 25% of cancers worldwide and around
10% in the United States, are caused by these invisible organisms.
• The majority of cancers, however, do not arise in relation to an infectious
organism, and in 1976 many cellular oncogenes were found to be
mutated proto-oncogenes; genes normally present in humans.
• Since that time much has been learned about how these genes (or the
proteins they code for) function, with some of the exciting advances in
cancer treatment derived from targeting the oncoproteins responsible for
cancer growth.

6. DISCOVERY AND
IDENTIFICATION

7. • The first oncogenes were discovered through the study of retroviruses,
RNA tumor viruses whose genomes are reverse-transcribed into DNA in
infected animal cells.
• During the course of infection, retroviral DNA is inserted into the
chromosomes of host cells. The integrated retroviral DNA, called the
provirus, replicates along with the cellular DNA of the host.
• Transcription of the DNA provirus leads to the production of viral progeny
that bud through the host cell membrane to infect other cells.
• Two categories of retroviruses are classified by their time course of tumor
formation in experimental animals.
• Acutely transforming retroviruses can rapidly cause tumors within days
after injection. These retroviruses can also transform cell cultures to the
neoplastic phenotype. Chronic or weakly oncogenic retroviruses can
cause tissue-specific tumors in susceptible strains of experimental animals
after a latency period of many months. Although weakly oncogenic
retroviruses can replicate in vitro, these viruses do not transform cells in
culture.

8. • Retroviral oncogenes are altered versions of host cellular
protooncogenes that have been incorporated into the retroviral
genome by recombination with host DNA, a process known as
retroviral transduction.
• This surprising discovery was made through study of the Rous
sarcoma virus (RSV) (Figure)

9. • RSV is an acutely transforming retrovirus first isolated from a chicken
sarcoma over 80 years ago by Peyton Rous.
• Studies of RSV mutants in the early 1970s revealed that the transforming
gene of RSV was not required for viral replication.
• Molecular hybridization studies then showed that the RSV transforming
gene (designated v-src) was homologous to a host cellular gene (c-src)
that was widely conserved in eukaryotic species.
• Studies of many other acutely transforming retroviruses from fowl, rodent,
feline, and nonhuman primate species have led to the discovery of dozens
of different retroviral oncogenes.
• In every case, these retroviral oncogenes are derived from normal cellular
genes captured from the genome of the host. Viral oncogenes are
responsible for the rapid tumor formation and efficient in vitro
transformation activity characteristic of acutely transforming retroviruses.

10. • In contrast to acutely transforming retroviruses, weakly
oncogenic retroviruses do not carry viral oncogenes. These
retroviruses, which include mouse mammary tumor virus (MMTV)
and various animal leukemia viruses, induce tumors by a process
called insertional mutagenesis (Figure)

11. • This process results from integration of the DNA provirus into the
host genome in infected cells. In rare cells, the provirus inserts
near a protooncogene.
• Expression of the protooncogene is then abnormally driven by the
transcriptional regulatory elements contained within the long
terminal repeats of the provirus.
• In these cases, proviral integration represents a mutagenic event
that activates a protooncogene.
• Activation of the protooncogene then results in transformation of
the cell, which can grow clonally into a tumor.

12. • The long latent period of tumor formation of weakly oncogenic
retroviruses is therefore due to the rarity of the provirus
insertional event that leads to tumor development from a single
transformed cell.
• Insertional mutagenesis by weakly oncogenic retroviruses, first
demonstrated in bursal lymphomas of chickens, frequently
involves the same oncogenes (such as myc, myb, and erb B)
that are carried by acutely transforming retroviruses.
• In many cases, however, insertional mutagenesis has been
used as a tool to identify new oncogenes, including int-1, int-2,
pim-1, and lck.22

13. • The demonstration of activated
protooncogenes in human tumors
was first shown by the DNA-
mediated transformation
technique.
• This technique, also called gene
transfer or transfection assay,
verifies the ability of donor DNA
from a tumor to transform a
recipient strain of rodent cells
called NIH 3T3, an immortalized
mouse cell line (Figure)

14. • This sensitive assay, which can detect the presence of single-copy
oncogenes in a tumor sample, also enables the isolation of the
transforming oncogene by molecular cloning techniques.
• After serial growth of the transformed NIH 3T3 cells, the human tumor
oncogene can be cloned by its association with human repetitive DNA
sequences. The first human oncogene isolated by the gene transfer
technique was derived from a bladder carcinoma.
• Overall, approximately 20% of individual human tumors have been
shown to induce transformation of NIH 3T3 cells in gene-transfer
assays. The value of transfection assay was recently reinforced by the
laboratory of Robert Weinberg, which showed that the ectopic
expression of the telomerase catalytic subunit (hTERT), in combination
with the simian virus 40 large T product and a mutated oncogenic H-
ras protein, resulted in the direct tumorigenic conversion of normal
human epithelial and fibroblast cells.

15. • Many of the oncogenes identified by gene-transfer studies are identical
or closely related to those oncogenes transduced by retroviruses. Most
prominent among these are members of the ras family that have been
repeatedly isolated from various human tumors by gene transfer.
• A number of new oncogenes (such as neu, met, and trk) have also
been identified by the gene-transfer technique.
• In many cases, however, oncogenes identified by gene transfer were
shown to be activated by rearrangement during the experimental
procedure and are not activated in the human tumors that served as the
source of the donor DNA, as in the case of ret that was subsequently
found genuinely rearranged and activated in papillary thyroid
carcinomas.

16. • Chromosomal translocations have served as guideposts for the
discovery of many new oncogenes.
• Consistently recurring karyotypic abnormalities are found in many
hematologic and solid tumors. These abnormalities include
chromosomal rearrangements as well as the gain or loss of whole
chromosomes or chromosome segments.
• The first consistent karyotypic abnormality identified in a human
neoplasm was a characteristic small chromosome in the cells of
patients with chronic myelogenous leukemia.
• Later identified as a derivative of chromosome 22, this abnormality
was designated the Philadelphia chromosome, after its city of
discovery. The application of chromosome banding techniques in the
early 1970s enabled the precise cytogenetic characterization of many
chromosomal translocations in human leukemia, lymphoma, and solid
tumors.

17. • The subsequent development of molecular cloning techniques then
enabled the identification of protooncogenes at or near chromosomal
breakpoints in various neoplasms.
• Some of these protooncogenes, such as myc and abl, had been
previously identified as retroviral oncogenes.
• In general, however, the cloning of chromosomal breakpoints has
served as a rich source of discovery of new oncogenes involved in
human cancer.

18. TYPES AND
EXAMPLES

19. • Different types of oncogenes have different effects on growth
(mechanisms of action), and to understand these it's helpful to look at
what is involved in normal cell proliferation (the normal growth and
division of cells).
• Most oncogenes regulate the proliferation of cells, but some inhibit
differentiation (the process of cells becoming unique types of cells) or
promote survival of cells (inhibit programmed death or apoptosis).
• Recent research also suggests that proteins produced by some
oncogenes work to suppress the immune system, reducing the chance
that abnormal cells will be recognized and eliminated by immune cells
such as T-cells.
• While there are more than 100 different functions of oncogenes, they can
be broken down into several major types that transform a normal cell to a
self-sufficient cancer cell. It's important to note that several oncogenes

20.  Growth Factors
• Some cells with oncogenes become self-sufficient by making
(synthesizing) the growth factors to which they respond.
• The increase in growth factors alone doesn't lead to cancer but can
cause rapid growth of cells that raises the chance of mutations.
• An example includes the proto-oncogene SIS, that when mutated
results in the overproduction of platelet-derived growth factor
(PDGF).
• Increased PDGF is present in many cancers, particularly bone
cancer (osteosarcoma) and one type of brain tumor.

21.  Growth Factor Receptors
• Oncogenes may activate or increase growth factor receptors on
the surface of cells (to which growth factors bind).
• One example includes the HER2 oncogene that results in a
significantly increased number of HER2 proteins on the surface of
breast cancer cells. In roughly 25% of breast cancers, HER2
receptors are found in numbers 40 times to 100 times higher than
in normal breast cells.
• Another example is the epidermal growth factor receptor (EGFR)
found in around 15% of non-small cell lung cancers.

22.  Signal Transduction Proteins
• Other oncogenes affect proteins involved in transmitting signals from
the receptor of the cell to the nucleus. Of these oncogenes, the ras
family is most common (KRAS, HRAS, and NRAS) found in roughly
20% of cancers overall. BRAF in melanoma is also in this category.
 Regulators of Apoptosis
• Oncogenes may also produce oncoproteins that reduce apoptosis
(programmed cell death) and lead to prolonged survival of the cells.
• An example is Bcl-2, an oncogene that produces a protein
associated with the cell membrane that prevents cell death
(apoptosis).

23.  Non-Receptor Protein Kinases
• Non-receptor protein kinases are also included in the cascade that
carries the signal to grow from the receptor to the nucleus.
• A well-known oncogene involved in chronic myelogenous leukemia is
the Bcr-Abl gene (the Philadelphia chromosome) caused by a
translocation of segments of chromosome 9 and chromosome 22.
When the protein produced by this gene, a tyrosine kinase, is
continually produced it results in a continuous signal for the cell to grow
and divide.

24.  Transcription Factors
• Transcription factors are proteins that regulate when cells enter, and
how they progress through the cell cycle.
• An example is the Myc gene that is overly active in cancers such as
some leukemias and lymphomas.
 Cell Cycle Control Proteins
• Cell cycle control proteins are products of oncogenes that can affect
the cell cycle in a number of different ways.
• Some, such as cyclin D1 and cyclin E1 work to progress through
specific stages of the cell cycle, such as the G1/S checkpoint.

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