Carcinogenesis II Flashcards
The ______gene as a tumor suppressor in FAP
The APC gene as a tumor suppressor in FAP
FAP is inherited in an ________
autosomal dominant fashion
where patients inherit one defective APC gene will be at higher risk (90% will develop colon cancer by age 50) to develop colon cancer
Cancer develops when the wild-type gene is lost by __________.
LOH in cells in adenomatous polyps of the colon during the first 20 years.
These benign adenomatous polyps may become malignant by LOH.
benign adenomatous polyps may become malignant by
LOH
Like RB, the APC gene was isolated by ________. The molecular information can be used clinically to identify _________.
positional cloning after it was mapped to chromosome 5q by genetic linkage and LOH studies.
high-risk patients for therapy.
The APC gene encodes a cytoplasmic protein that regulates ________.
the localization of the Beta-catenin protein
Beta-catenin is kept at the plasma membrane by being bound to_______.
E- cadherin in normal cells
The APC protein causes the degradation of _______.
any unbound and free Beta-catenin in the cytoplasm
When the APC is lost in FAP patients,_________.
Beta-catenin goes to the nucleus to produce transcription of oncogenes like c-myc
Loss of APC tumor suppressor causes an ________
overexpression of the c-myc oncogene, resulting in cancer
In Breast and ovarian cancers, there are two similar predisposing genes:
BRCA1 and BRCA2
About _____% of woman with breast cancers have inherited mutations in the BRCA1 or 2 genes.
5%
Inherited cases of BRCA1/2 mutation display _____.
LOH and have only mutant BRCA1 or 2 genes
In the acquired cases of BRCA1/2, the situation is different from that seen for RB in that _______.
somatic mutations in these genes have not been found in tumors
Therefore, it is believed that mutations in other genes may affect BRCA1 and BRCA2 function indirectly.
Both BRCA1 and BRCA2 _________ may give rise to the many mutations needed for full-blown malignancy.
function in DNA repair and their loss
BRCA2 has been shown to be allelic with________. This means that individuals with homozygous mutations in BRCA2 get _______, while heterozygotes get ______
Fanconi’s anemia D1 gene, FANCD1
Fanconi’s anemia
breast cancer from rare recombinant cells in the mammary gland that lose the wild-type allele.
mutant p53 is found in about __% of all cancers
50%
p53 is a ______.
It also is important for the response of cells to environmental mutagenesis.
tumor suppressor gene.
response of cells to environmental mutagenesis
Cells missing p53 accumulate ________.
mutations at a muchhigher rate and thereby, have a greater chance of becoming malignant
p53 as a guardian of the genome
preventing potentially deleterious mutations.
In p53 defective cells, damaged DNA is replicated, thereby producing additional mutations including chromosomal rearrangements, which can lead to cancer
The p53 gene was initially found to be an _________.
oncogene, in that certain p53 mutant genes were dominant to the wild-type gene in producing cellular transformation
p53 acts as a classic tumor suppressor in _____
How?
Li-Fraumeni syndrome.
The oncogenic p53 mutations produce a mutant p53 protein that can bind the wild-type p53 protein and inactivate it. These “dominant-negative” p53 mutations can be viewed as “spoilers” or “monkey wrenches”.
p53 protein acts as a transcription factor important for the expression of genes, which prevent cells from
from replicating damaged or foreign DNA
_____is also required for apoptosis, in which cells commit suicide if their DNA is damaged beyond repair.
p53
p53 “hotspots”.
Some point mutations of p53 are found more frequently than others.
mutational “hotspots” produce alterations in amino acids 248 or 273 of p53 in all human cancers.
Some “hotspots” are unique to specific cancers.
an alteration in amino-acid 157 of p53 is found mainly in
lung cancer and is the result of the mutagenic chemicals found in cigarette smoke
p53 interferes with the life cycle of many human viruses including ______.
Adenovirus and HPV (human papilloma virus)
The viruses have oncogenes that act by ______,
examples:
inactivating p53
Adenovirus E1B and HPV E6 proteins
Remember that these viruses also inactivate RB protein. In fact, destruction of both RB and p53 either by cellular mutations or viruses is a major route to cancer.
APC is part of a protein complex that binds ______
beta-catenin in the cytoplasm
Normally, beta-catenin is either _______.
phosphorylated and targeted for ubiquitination and degradation or is released into the nucleus when Wnt signaling molecules bind to a cell surface receptor called frizzled
In the absence of normal APC, beta-catenin is ________
free to translocate into the nucleus and activate transcription factors on oncogenes (such as c-myc) without regulation by Wnt signaling.
APC is functioning as a tumor suppressor by ________.
inhibiting the activation of oncogenic transcription factors by beta-catenin
Loss of APC is found in patients with ______
Familial Adenomatous Polyposis (FAP).
BRCA1 and BRCA2 function to ________.
suppress uncontrolled cell proliferation by repairing damaged DNA.
The BRCA1 protein is a scaffold for protein complexes involved in _______
various DNA checkpoints. BRCA2 binds Rad51 and repairs double strand breaks.
The ability of a mutated p53 gene to show dominance over the wild-type allele is due to a ________
dominant-negative effect
dominant-negative effect of p53:
p53 forms a tetrameric protein (four p53s in a complex) in the cell and a mutated p53 will bind to other wild- type proteins in this complex and inactivate them.
p53 acts as a transcription factor to ______.
inhibit replication of damaged DNA
When damaged DNA is detected at DNA checkpoints, p53 ______.
induces apoptosis or cell cycle arrest
Cell cycle arrest is achieved through _______
multiple pathways, which prevent the cell from entering into the S or M phase of the cell cycle until the DNA is repaired.
Certain viruses make proteins that specifically target Rb and p53 to ________.
These proteins either _________.
disrupt their ability to effectively suppress tumor formation
inactivate Rb and p53 or target them for degradation
Adenovirus, makes proteins E1A and E1B which target:
E1A: Rb
E1B: p53
Human papilloma virus is an ___________
oncogenic virus in that it produces proteins that disrupt the activity of the tumor suppressors Rb and p53.
HPV protein E7 binds to ________.
binds to and inactivates Rb, which pushes the cell to move forward through the cell cycle.
HPV protein E6 function
ubiquitinates p53, targeting it for degradation.
