Anon cogen e is a protein-encodinggene which, when deregulated, participates in the
onset and development ofcancer. Many cells normally undergo a programmed form of
death (apoptosis). Activated oncogenes can cause those cells to survive and proliferate
instead.Most oncogenes require an additional step, such as mutations in another gene, or
environmental factors, such as viral infection, to cause cancer. Since the 1970s, dozens of
oncogenes have been identified in human cancer. Many cancer drugs target those DNA
sequences and their products.
Ap roto-on cogen e is a normal gene that can become anoncogene due to mutations or
increasedexpres s ion. Proto-oncogenes code forproteins that help to regulate cell growth
anddifferentiat ion. Proto-oncogenes are often involved in signal transduction and
execution ofmitogenic signals, usually through theirprotein products. Uponactivation, a
proto-oncogene (or its product) becomes a tumor-inducing agent, an oncogene.Examples
of proto-oncogenes includeRAS,WN T,MYC,ERK andTRK.
original function. There are three basic activation types:
1)Amutation within a proto-oncogene can cause a change in the protein structure.
2)An increase in protein concentration
3)A chromosomal translocation (another type of chromosome abnormality
********************************************************************************************************* The 2 main types of genes that are now recognized as playing a role in cancer areo nco ge ne s and tumor suppressor genes.
degree to which it differentiates (or specializes). When a proto-oncogene mutates (changes) into
an oncogene, it becomes permanently "turned on" or activated when it is not supposed to be.
When this occurs, the cell divides too quickly, which can lead to cancer.
It may be helpful to think of a cell as a car. For it to work properly, there need to be ways to
control how fast it goes. A proto-oncogene normally functions in a way that is similar to a gas
pedal -- it helps the cell grow and divide. An oncogene could be compared to a gas pedal that is
stuck down, which causes the cell to divide out of control.
When they are "on," they stimulate the cell to grow. Certain mutations in the genes that
produce these cause them to always be "on." In other cases, the genes area mp lif ied.
This means that instead of the usual 2 copies of the gene, there may be several extras,
resulting in too many growth factor receptor molecules. As a result, the cells become
overly sensitive to growth-promoting signals. The best known examples of growth factor
receptor gene amplification are erb B and erb B-2. These are sometimes known as
epidermal growth factor receptor and HER2/neu. HER2/neu gene amplification is an
important abnormality seen in about one third of breast cancers. Both of these
oncogenes are targets of newly developed anti-cancer treatments.
receptor and the cell nucleus where the signal is received. Like growth factor receptors,
these can be turned on or off. When they are abnormal in cancer cells, they are turned
on. Two well known signal transducers are abl and ras. Abl is activated in chronic
myelocytic leukemia and is the target of the most successful drug for this disease,
imatinib or Gleevec. Abnormalities of ras are found in many cancers.
divide. These molecules act on the DNA and control which genes are active in producing
RNA and protein. The best known of these is calledmyc. In lung cancer, leukemia,
lymphoma, and a number of other cancer types, myc is often overly activated and
stimulates cell division.
suicide when it becomes abnormal. When these genes are overactive they prevent the
cell from going through the suicide process. This leads to an overgrowth of abnormal
cells, which can then become cancerous. The most well described one is calledbcl- 2. It
is often activated in lymphoma cells.
As scientists learn more about oncogenes, they may be able to develop drugs that inhibit or stop
them. Many agents that target oncogenes are currently in development as potential anticancer
drugs, and some have already been approved by the US Food and Drug Administration (FDA) for
clinical use, as we will discuss in more detail later on in this document.
and tell cells when to die (a process known asap op to sis or programmed cell death). When tumor
suppressor genes don\u2019t work properly, cells can grow out of control, which can lead to cancer.
About 30 tumor suppressor genes have been identified, including p53, BRCA1, BRCA2, APC,
A tumor suppressor gene is like the brake pedal on a car \u2013 it normally keeps the cell from dividing too quickly just as a brake keeps a car from going too fast. When something goes wrong with the gene, such as a mutation, cell division can get out of control.
An important difference between oncogenes and tumor suppressor genes is that
oncogenes result from theac ti va ti on (turning on) of proto-oncogenes, but tumor
suppressor genes cause cancer when they arei na c tiv a te d (turned off). Another major
difference is that while the overwhelming majority of oncogenes develop from mutations
in normal genes (proto-oncogenes) during the life of the individual (acquired mutations),
abnormalities of tumor suppressor genes can be inherited as well as acquired.
growth and reproduction. TheRB1 (retinoblastoma) gene is an example of such a gene.
Abnormalities of the RB1 gene can lead to a type of eye cancer (retinoblastoma) in
infants, as well as to other cancers.
Because all our chromosomes are paired, there are always 2 copies of each gene. But
the inherited RB1 mutation only affects one of the gene pairs. In this situation there is no
cancer. The person has one good gene and one mutated one and is therefore said to be
heterozygous for the trait coded into that gene pair. Then during the infant\u2019s
development, a random mutation can occur in the normal copy of the RB1 gene.
Scientists call this process loss of heterozygosity (LOH), and it applies to most
abnormalities in tumor suppressor genes. As long as one copy of the gene is normal, no
cancer develops. But when the other copy mutates, even in one cell, then cancer can
start to develop. Evidently, these mutations occur often, but we are protected as long as
one of the pair in the cell is normal.
repairing DNA damage. Every time a cell prepares to divide into 2 new cells, it must
duplicate its DNA. This process is not perfect, and copying errors sometimes occur.
Fortunately, cells have DNA repair genes, which make proteins that proofread DNA. But
if the genes responsible for the repair are faulty, then the DNA can develop abnormalities
that may lead to cancer. When DNA repair genes don\u2019t work, mutations can slip by,
allowing oncogenes and abnormal tumor suppressor genes to be produced. The genes
responsible for HNPCC (hereditary nonpolyposis colon cancer) are examples of DNA
repair gene defects. When these genes do not repair the errors in DNA, HNPCC can
result. HNPCC accounts for up to 5% of all colon cancers and some endometrial cancers.
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