Oncosuppressor genes petronini Flashcards
In an experiment, a normal cell (normal fibroblast) has been fused with a cancer cell line derived
from a uterine cervix carcinoma. A hybrid has been obtained: a cell composed of the DNA of the normal
cell and the tumor cell
Did the cell become cancerous?
The behaviour of the hybrid cell is normal, not neoplastic.
At least initially it works normally because in normal cell there is something that inhibits the
growth of the hybrid cell.
The problem occurs when hybrid loses
chromosome 13: if cell loses this chromosome the behaviour becomes neoplastic.
So, the chromosome 13 contains genes whose products are called tumour-suppressor.
If this chromosome is reinserted the behaviour is normal.
This is the first explanation of the presence of brakes in cells.
Retinoblastoma:
Retinoblastoma is a cancer that affects the precursor retinoblasts of photoreceptors.
There are two forms of this tumor:
* Early familial form (40% of cases)
* Late sporadic form (60% of cases)
Cytogenetic studies have shown the presence of a band deletion characteristic on the long arm of
chromosome __________ in retinoblastoma and on this part of the chromosome there is the Rb gene, codifying
for Rb protein
13(q14)
In __________ form there is a deletion in all cells of the body, meaning that this deletion is inherited.
familial
In __________ form, the deletion is only present in tumor cells.
sporadic
In hereditary retinoblastoma (familial form)
the first mutation is present in the _________, so the
cells of all tissues of the child are all
heterozygous for this mutation
germline
A single
additional mutation is enough to inactivate both
alleles and give rise to the tumour. The first
mutation is prezygotic, the second one is
postzygotic.
In non-hereditary retinoblastoma (sporadic
form) the germline is without mutations, both
work correctly. The first and second mutations
are _____________ and probability is lower than
familial retinoblastoma in which was enough
just one mutation because here are necessary
two mutations in the same cell.
The offspring of this child has no risk of
retinoblastoma because he doesn’t carry any
mutant allele
postzygotic
Knudson’s “Two-Hit” Theory of Cancer Causation
We have seen that we need two hits to inactivate onco-suppressor and develop retinoblastoma (Knudson’s “Two-Hit” Theory of Cancer Causation).
The normal gene balances the mutated one, so the
phenotype is normal.
In the scheme, above, we have nonhereditary
retinoblastoma, in which we start form a normal cell, cell is
hit by first mutation (one-hit cell) and so only one allele
becomes mutated, cell is hit again by a second mutation
(two-hit cell) and also the other allele becomes mutated:
retinoblastoma gene.
Below there is hereditary retinoblastoma in which the first mutation is in the germ line and the second
gives rise to retinoblastoma.
In the S phase of chromosome replication, we have normal and mutant alleles (heterozygosity of the Rb
gene). After ___________ and _____________ of chromatids, there can be retention of Rb
heterozygosity in daughter cells or loss of Rb heterozygosity in which cell lacks any functional
Rb gene copies.
mitotic recombination, segregation
___________ has a dominant phenotypic
expression, only one allele is mutated and so an oncogene is obtained. In the last lesson, we saw it
happens because of point mutation, amplification of
the gene, or translocation
Proto-oncogene
which chromosome is p53 gene is located on?
17
is one mutated allele is enough for p53 to become an oncogene?
yes
____________ gene, inactivated by double hits, has recessive phenotypic expression, due to
inactivating mutation, deletion, and repression by hypermethylation (epigenetics) of the cytosine of
the promoter of the gene
Onco-suppressor
Rb, when present in the hypophosphorylated state, binds the
transcription factor _______, so that the cell is
blocked in G1 phase.
When Rb is hyper-phosphorylated
byCDK4/6, it releases _______,
E2F, which
binds to promoters of genes like DNA
polymerase, Thymidylate synthase,
Ribonucleotide reductase, Cyclin E,
Dihydrofolate reductase.
Products of these genes are important for moving to S phase.
If Rb protein is not present because of deletion of one allele or, for example, hypermethylation of the
second allele, E2F is free so proliferation of the cell is not regulated.
in the structure of the P53 ____________ domain is the region
affected by mutation so that it
becomes unable to bind DNA and
therefore unable of inducing
transcription of genes involved in cell
cycle arrest, apoptosis.
DNA binding
There are also transactivation domain, proline-rich domain, and tetramerization domain.
At molecular level, when there is DNA damage, there is
kinase called ATM, mutated in the disease Ataxia
telangiectasia, which phosphorylates p53, which performs functions like?
- Phosphorylated p53 is stable and accumulates,
inducing transcription of p21 (remember CDK
inhibitors: p16, p21, p27), which induces
proliferative arrest. - Can also induce expression of GADD45 (growth
arrest DNA damage), which induces DNA repair. - If damage is repaired, mdm2 accumulates and
inhibits p53: cell restart proliferation. - If the damage is not repaired, p53 induces cell death by increasing expression of BAX, a
pro-apoptotic protein
One of the most important transcriptional targets of p53 is _____. It can promote temporary arrest,
therefore quiescence of the cell cycle, or permanent arrest, therefore senescence.
p21
