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Summary SSA7 Tumor Suppressor Genes
Summary and WGs answers of SSA7 Tumor Suppressor Genes of the course MBO (molecular biology and oncology) at Leiden University.
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SSA7 Tumor Suppressor GenesChapter 7 Weinberg
Oncoproteins are often part of a growth stimulatory signaling pathway. The antigrowth genes
are the tumor suppressor genes. Inactivation of tumor suppressor genes also plays a role in
cancer pathogenesis.
7.1 Cell fusion experiments indicate that the cancer
phenotype is recessive
Oncogenes act in a dominant fashion. Fusion experiments
revealed that it is not always the case. Fusing agents can be
chemicals or viral glycoproteins. A syncytium is a cell with a
single cytoplasm and two nuclei. A polykaryon is a giant
multinucleated cell. A heterokaryon is created when two cells of
different origins are fused. Cells with two nuclei are viable and
when they go through their first round of division, there will be
only one nuclear membrane leading to a tetraploid nucleus. After
many divisions they can shed chromosomes.
It was showed that fusing a cancer cell with a normal cell lead to
loss of malignant phenotype.
7.2 The recessive nature of the cancer cell
phenotype requires a genetic explanation
The inactive alleles is recessive in the presence of an intact, wild-type allele. If growth
repressors are lost, proliferation of cancer cells accelerates. As long as the cells lacks these
genes, this continues. It is easier to inactivate a gene to make it inactive than to make it more
active. A tumor cell only benefits from inactivation of a tumor suppressor gene when both
alleles are inactivated. Cells with only one are aspiring tumor cells.
7.3 Retinoblastoma tumor provides a solution to the genetic
puzzle of tumor suppressor genes
Retinoblastoma is a tumor syndrome. Children can be from families with no history of
retinoblastoma and present with single tumors in one eye (sporadic). However, there are also
familial forms which lead to bilateral retinoblastoma and this is vet likely to come back. Also
increases risk of osteosarcoma. However, this form can also occur in children with no family
history when there is a de novo mutation int the gametes. The familial form is caused by a
hereditary mutation in the Rb gene (first hit) a second hit in which the remaining Rb gene is
also inactivated (which is very common) can then lead to formation of the cancer.
You could say that the Rb gene is both dominant and recessive. Mutant Rb acts dominantly
when looking at the whole organism, but recessively when looking at a single cell. It is
dominant as the likelihood of losing a wild type allele is pretty high.
7.4 Incipient cancer cells invent ways to eliminate wild-type
copies of tumor suppressor genes
It is not always the case that the second mutation occurs by an independent event. There are
recombinations that can occur during mitosis (mitotic recombination). Arms of chromsomes
can be exchanged which can lead to loss of heterozygosity (LOH). This can cause a cell to
, now have two inactive Rb alleles. Normal mutational event occur only about 10-12 cell per
generation. This mitotic recombination has a higher frequency; 10-5 to 10-4. The second
mutation in the Rb gene seemed to occur 10-6 per cell generation. Endogamy can lead to
higher rates of LOH as there is more homology between the chromosomes making mitotic
recombination more likely to occur.
Another way in which cells can achieve LOH is
via gene conversion. During replication, the
DNA polymerase can jump between strands of
the different homologous chromosomes (copy
choice).
LOH can also occur by breaking of a
chromosomal segment which is not replaced
which results in hemizygosity. Cells can
survive with this.
In many tumor LOH seems to be achieved by nondisjunction. If the third chromosome which
then contained the wild type allele is lost, this also
leads to two abnormal Rb copies.
7.5 The Rb gene often undergoes
loss of heterozygosity in tumors
Rb is localized on 13q14. Another gene that lies here
is enzyme esterase D. Because the Rb gene was
still unknown, they used this gene as a surrogate for their hypothesis that there is LOH of the
Rb gene in retinoblastoma. This was indeed the case.
7.6 Loss of heterozygosity events can be used to find tumor
suppressor genes
TSGs have the tendency to undergo LOH. As the chromosomal region flanking the TSG
seemed to undergo the LOH with the TSG itself, you could identify genetic markers that
undergo the LOH and then exploit that specific DNA segment further. Some polymorphisms
permit of disallow cleavage by certain restriction enzymes and these can be used as
markers; restriction fragment length polymorphism (RFLP).These experiments showed that
the p arm of 17 and the q arm of 18 underwent LOH exceptionally often in cancer. A newer
technique to identify LOH is SNP arrays. Via this technique CDKN2A and CDKN2B were
discovered which are on chromosome 9.
7.7 Many familial cancer can be explained by inheritance of
mutant tumor suppressor genes
Tumor suppressor genes function to directly control the biology of cells by affecting
proliferation, differentiation and survival. Genes that function in this way are called the
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