A tumor suppressor gene, or antioncogene, is a gene that protects a cell from one step
on the path to cancer.
When this gene mutates to cause a loss or reduction in its function, the cell can progress
to cancer, usually in combination with other genetic changes.
The loss of these genes may be even more important than proto-oncogene/oncogene activation for
the formation of many kinds of human cancer cells.
Tumor suppressor genes can be grouped into categories including caretaker genes, gatekeeper
genes, and landscaper genes; the classification schemes are evolving as medicine advances,
learning from fields including molecular biology, genetics, and epigenetics.
Two-hit hypothesis
Unlike oncogenes, tumor suppressor genes generally follow the "two-hit hypothesis," which implies
that both alleles that code for a particular protein must be affected before an effect
is manifested.
This is because if only one allele for the gene is damaged, the second can still produce
the correct protein.
In other words, mutant tumor suppressors' alleles are usually recessive whereas mutant
oncogene alleles are typically dominant.
The two-hit hypothesis was first proposed by A.G. Knudson for cases of retinoblastoma.
Knudson observed that the age of onset of retinoblastoma followed 2nd order kinetics,
implying that two independent genetic events were necessary.
He recognized that this was consistent with a recessive mutation involving a single gene,
but requiring biallelic mutation.
Oncogene mutations, in contrast, generally involve a single allele because they are gain-of-function
mutations.
There are exceptions to the "two-hit" rule for tumor suppressors, such as certain mutations
in the p53 gene product.
p53 mutations can function as a "dominant negative," meaning that a mutated p53 protein
can prevent the function of normal protein from the un-mutated allele.
Other tumor-suppressor genes that are exceptions to the "two-hit" rule are those that exhibit
haploinsufficiency, including PTCH in medulloblastoma and NF1 in neurofibroma.
An example of this is the p27Kip1 cell-cycle inhibitor, in which mutation of a single allele
causes increased carcinogen susceptibility.
Functions Tumor-suppressor genes, or more precisely,
the proteins they code for, either have a dampening or repressive effect on the regulation
of the cell cycle or promote apoptosis, and sometimes do both.
The functions of tumor-suppressor proteins fall into several categories including the
following: Repression of genes that are essential for
the continuing of the cell cycle.
If these genes are not expressed, the cell cycle does not continue, effectively inhibiting
cell division.
Coupling the cell cycle to DNA damage.
As long as there is damaged DNA in the cell, it should not divide.
If the damage can be repaired, the cell cycle can continue.
If the damage cannot be repaired, the cell should initiate apoptosis to remove the threat
it poses for the greater good of the organisms produced
Some proteins involved in cell adhesion prevent tumor cells from dispersing, block loss of
contact inhibition, and inhibit metastasis.
These proteins are known as metastasis suppressors.
DNA repair proteins are usually classified as tumor suppressors as well, as mutations
in their genes increase the risk of cancer, for example mutations in HNPCC, MEN1 and BRCA.
Furthermore, increased mutation rate from decreased DNA repair leads to increased inactivation
of other tumor suppressors and activation of oncogenes.
Examples The first tumor-suppressor protein discovered
was the Retinoblastoma protein in human retinoblastoma; however, recent evidence has also implicated
pRb as a tumor-survival factor.
Another important tumor suppressor is the p53 tumor-suppressor protein encoded by the
TP53 gene.
Homozygous loss of p53 is found in 65% of colon cancers, 30–50% of breast cancers,
and 50% of lung cancers.
Mutated p53 is also involved in the pathophysiology of leukemias, lymphomas, sarcomas, and neurogenic
tumors.
Abnormalities of the p53 gene can be inherited in Li-Fraumeni syndrome, which increases the
risk of developing various types of cancers.
PTEN acts by opposing the action of PI3K, which is essential for anti-apoptotic, pro-tumorogenic
Akt activation.
As costs of DNA sequencing have diminished, many cancers have now been sequenced for the
first time, revealing novel tumor suppressors.
Among the most frequently mutated genes are components of the SWI/SNF chromatin remodeling
complex, which are lost in about 20% of tumors.
Other examples of tumor suppressors include pVHL, APC, CD95, ST5, YPEL3, ST7, and ST14.
See also Metastasis suppressor
Adenomatosis polyposis coli Oncogene
Cancer DNA repair
Signal transduction Von Hippel Lindau Binding protein 1
BRCA1 p53
References
External links TCF21 gene discovery at Ohio State University
Drosophila Oncogenes and Tumor Suppressors - The Interactive Fly
Online book: Tumor Suppressor Genes, published in 2012
Tumor Suppressor Gene Database, published in 2012