A CLEAR EXPLANATION OF TUMOR SUPRESSOR GENES AND explanation of different examples and cancers about them

1. TUMOR SUPRESSOR GENES
D.INDRAJA

2. • A tumor suppressor gene, or anti-oncogene, is a gene that regulates a cell during cell division and
replication
• Tumor suppressor genes are normal genes that slow down cell division, repair DNA mistakes, or tell
cells when to die (a process known as apoptosis or programmed cell death). When tumor suppressor
genes don't work properly, cells can grow out of control, which can lead to cancer.
• An important difference between oncogenes and tumor suppressor genes is that oncogenes result from
the activation (turning on) of proto-oncogenes, but tumor suppressor genes cause cancer when they
are inactivated (turned off)
• The loss of function for these genes may be even more significant in the development of human cancers,
compared to the activation of oncogenes.
• Tumor suppressor genes (TSGs) can be grouped into the following categories:
• caretaker genes  ensure stability of the genome via DNA repair and subsequently when mutated allow
mutations to accumulate
• gatekeeper genes  regulate cell growth by either inhibiting cell cycle progression or inducing apoptosis
• landscaper genes  regulate growth by contributing to the surrounding environment, when mutated can
cause an environment that promotes unregulated proliferation.

3. History
• Dr. Harris’s experiments, tumor cells were fused with normal somatic cells to make hybrid cells. Each
cell had chromosomes from both parents and upon growth, a majority of these hybrid cells did not have
the capability of developing tumors within animals.
• The suppression of tumorigenicity in these hybrid cells prompted researchers to hypothesize
that genes within the normal somatic cell had inhibitory actions to stop tumor growth.
• This initial hypothesis eventually lead to the discovery of the first classic tumor suppressor gene
by Alfred Knudson, known as the Rb gene, which codes for the retinoblastoma tumor suppressor protein
Two-hit hypothesis
• The Knudson hypothesis, also known as the two-hit hypothesis, is the hypothesis that most tumor
suppressor genes require both alleles to be inactivated, either through mutations or through epigenetic
silencing, to cause a phenotypic change
• Knudson performed a statistical analysis on cases of retinoblastoma, a tumor of the retina that occurs
both as an inherited disease and sporadically.
• He noted that inherited retinoblastoma occurs at a younger age than the sporadic disease. In addition, the
children with inherited retinoblastoma often developed the tumor in both eyes
• Knudson suggested that two "hits" to DNA were necessary to cause the cancer. In the children with
inherited retinoblastoma, the first mutation in what later came to be identified as the RB1 gene, was
inherited, the second one acquired. In non-inherited retinoblastoma, instead two mutations, or "hits", had
to take place before a tumor could develop, explaining the later onset.

4. • Some tumor suppressor genes have been found to be "dose-dependent" so that inhibition of one copy of
the gene (either via genetic or epigenetic modification) may encourage a malignant phenotype, which is
termed haploinsufficiency

6. Retinoblastoma gene
• RB protein- product of RB gene
• Key role in regulation of the cell cycle
• “Governor” of the cell cycle
In general
activation

7. In hypo phosphorylated
form
When hyperphosphorylated

8. • First phenotypic cancer suppressor gene to be discovered
• Responsible for retinoblastoma, a malignant tumor of retina, a rare childhood tumor
• 60% are sporadic (non-inherited), remaining ones are familial

9. P53 gene
• One of the most important tumor suppressors is tumor protein p53, which plays a key role in the
cellular response to DNA damage.
• It is called as guardian of the genome
• p53 acts primarily at the G 1checkpoint (controlling the G1 to S transition), where it blocks cell cycle
progression in response to damaged DNA and other unfavorable conditions
• When a cell’s DNA is damaged, a sensor protein activates p53, which halts the cell cycle at the G1
checkpoint by triggering production of a cell-cycle inhibitor.
• This pause buys time for DNA repair, which also depends on p53, whose second job is to activate DNA
repair enzymes.
• If the damage is fixed, p53 will release the cell, allowing it to continue through the cell cycle.
• If the damage is not fixable, p53 will play its third and final role: triggering apoptosis (programmed cell
death) so that damaged DNA is not passed on

11. • In cancer cells, p53 is often missing, nonfunctional, or less active than normal. For example, many
cancerous tumors have a mutant form of p53 that can no longer bind DNA.
• When p53 is defective, a cell with damaged DNA may proceed with cell division. The daughter cells of
such a division are likely to inherit mutations due to the unrepaired DNA of the mother cell. Over
generations, cells with faulty p53 tend to accumulate mutations, some of which may turn proto-
oncogenes to oncogenes or inactivate other tumor suppressors.

12. • P53 can lost its function by:
• Non-sense mutation or mis-sense mutation
• Complex of normal p53 and mutant p53 inactivating the function of normal allele
• Binding of normal p53 to viral oncoproteins

13. Li- Fraumeni syndrome
• Li- Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome.
• This means that a person who has LFS will have an increased risk of developing cancer.
• Common type of cancer found in LFS- bone cancer, breast cancer, brain cancer
• Affected individuals Carry germ line mutation in one p53 allele, but tumors display mutation at both
alleles
• Another example of two-hit hypothesis

14. APC Gene
• Implicated in familial adenomatous polyposis coli and most sporadic colorectal cancers
• β-catenin- is a dual function protein, tissue formation & helps to control the activity(expression) of other
gene & promote cell growth & division.
• In humans, β-catenin is encoded by the CTNNB1 gene
• Excess of β-catenin promotes uncontrolled growth & division of cells
• APC binds to and inhibits the function of β-catenin
• Mutant APC is unable bind β-catenin to down regulate its activity & produce desmoid tumor

15. BRCA1 and BRCA2
• These are tumor suppressor genes and are involved in DNA repair of double-strand breaks.
• Breast (BR) cancer (CA) susceptibility genes, also incriminated in some ovarian cancers
• Involved in G1 check point
• Block entry of cell into S phase, particularly by inducing CDK inhibitor
• Promote DNA repair by binding to RAD5
• Mutations in BRCA1 (chromosome 17) and/or BRCA2 (chromosome 13) cause decreased stability of
the human genome and result in dangerous gene rearrangements that can lead to hematologic cancers.
• A BRCA mutation is a mutation in either of the genes, BRCA1 and BRCA2.
• Heterozygous germline mutations in either the BRCA1 or BRCA2 genes - high risk for breast and
ovarian cancer phenotypes - exhibit loss of heterozygosity (LOH).