Tumor suppressor
genes code for anti-proliferation signals and proteins that
suppress mitosis and cell growth. Generally, tumor suppressors
are transcription factors that are activated by cellular stress
or DNA damage. Often DNA damage will cause the presence of
free-floating genetic material as well as other signs, and will
trigger enzymes and pathways which lead to the activation of
tumor suppressor genes. The functions of such genes is to arrest
the progression of the cell cycle in order to carry out DNA
repair, preventing mutations from being passed on to daughter
cells. The p53 protein, one of the most important studied tumor
suppressor genes, is a transcription factor activated by many
cellular stressors including hypoxia and ultraviolet radiation
damage.
Despite nearly half of all cancers possibly involving
alterations in p53, its tumor suppressor function is poorly
understood. p53 clearly has two functions: one a nuclear role as
a transcription factor, and the other a cytoplasmic role in
regulating the cell cycle, cell division, and apoptosis.
The Warburg hypothesis is the preferential use of glycolysis for
energy to sustain cancer growth. p53 has been shown to regulate
the shift from the respiratory to the glycolytic pathway.
However, a mutation can damage the tumor suppressor gene itself,
or the signal pathway which activates it, "switching it off".
The invariable consequence of this is that DNA repair is
hindered or inhibited: DNA damage accumulates without repair,
inevitably leading to cancer.
Mutations of tumor suppressor genes that occur in germline cells
are passed along to offspring, and increase the likelihood for
cancer diagnoses in subsequent generations. Members of these
families have increased incidence and decreased latency of
multiple tumors. The tumor types are typical for each type of
tumor suppressor gene mutation, with some mutations causing
particular cancers, and other mutations causing others. The mode
of inheritance of mutant tumor suppressors is that an affected
member inherits a defective copy from one parent, and a normal
copy from the other. For instance, individuals who inherit one
mutant p53 allele (and are therefore heterozygous for mutated
p53) can develop melanomas and pancreatic cancer, known as Li-Fraumeni
syndrome. Other inherited tumor suppressor gene syndromes
include Rb mutations, linked to retinoblastoma, and APC gene
mutations, linked to adenopolyposis colon cancer. Adenopolyposis
colon cancer is associated with thousands of polyps in colon
while young, leading to colon cancer at a relatively early age.
Finally, inherited mutations in BRCA1 and BRCA2 lead to early
onset of breast cancer.
Development of cancer was proposed in 1971 to depend on at least
two mutational events. In what became known as the Knudson
two-hit hypothesis, an inherited, germ-line mutation in a tumor
suppressor gene would only cause cancer if another mutation
event occurred later in the organism's life, inactivating the
other allele of that tumor suppressor gene.[19]
Usually, oncogenes are dominant, as they contain
gain-of-function mutations, while mutated tumor suppressors are
recessive, as they contain loss-of-function mutations. Each cell
has two copies of the same gene, one from each parent, and under
most cases gain of function mutations in just one copy of a
particular proto-oncogene is enough to make that gene a true
oncogene. On the other hand, loss of function mutations need to
happen in both copies of a tumor suppressor gene to render that
gene completely non-functional. However, cases exist in which
one mutated copy of a tumor suppressor gene can render the
other, wild-type copy non-functional. This phenomenon is called
the dominant negative effect and is observed in many p53
mutations.
Knudson’s two hit model has recently been challenged by several
investigators. Inactivation of one allele of some tumor
suppressor genes is sufficient to cause tumors. This phenomenon
is called haploinsufficiency and has been demonstrated by a
number of experimental approaches. Tumors caused by
haploinsufficiency usually have a later age of onset when
compared with those by a two hit process.
Pathophysiology Cancer cell
biology >>
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Cancer
Classification
1. Nomenclature
2. Adult cancers
3. Childhood cancers
Signs and symptoms
Diagnosis
1. Investigation
2. Biopsy
Treatment
1. Surgery
2. Radiation therapy
3. Chemotherapy
4. Targeted therapies
5. Immunotherapy
6. Hormonal therapy
7. Symptom control
8. Complementary and alternative
9. Treatment trials
Prognosis
1. Emotional impact
Causes
1. Chemical carcinogens
2. Ionizing radiation &
Infectious diseases
3. Hormonal imbalances
& Immune system dysfunction
4. Heredity & Other causes
Pathophysiology
1. Epigenetics
2. Oncogenes
3. Tumor suppressor genes
4. Cancer cell biology
4.1 Clonal evolution
4.2 Biological properties of cancer cells
Prevention
1. Modifiable ("lifestyle") risk factors
2. Diet
3. Vitamins
4. Chemoprevention
5. Genetic testing
6. Vaccination
7. Screening
Epidemiology
History
Research |
