Carcinogenesis II

Question 1

The ______gene as a tumor suppressor in FAP

Answer 1

The APC gene as a tumor suppressor in FAP

Question 2

FAP is inherited in an ________

Answer 2

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

Question 3

Cancer develops when the wild-type gene is lost by __________.

Answer 3

LOH in cells in adenomatous polyps of the colon during the first 20 years.

These benign adenomatous polyps may become malignant by LOH.

Question 4

benign adenomatous polyps may become malignant by

Answer 4

LOH

Question 5

Like RB, the APC gene was isolated by ________. The molecular information can be used clinically to identify _________.

Answer 5

positional cloning after it was mapped to chromosome 5q by genetic linkage and LOH studies.

high-risk patients for therapy.

Question 6

The APC gene encodes a cytoplasmic protein that regulates ________.

Answer 6

the localization of the Beta-catenin protein

Question 7

Beta-catenin is kept at the plasma membrane by being bound to_______.

Answer 7

E- cadherin in normal cells

Question 8

The APC protein causes the degradation of _______.

Answer 8

any unbound and free Beta-catenin in the cytoplasm

Question 9

When the APC is lost in FAP patients,_________.

Answer 9

Beta-catenin goes to the nucleus to produce transcription of oncogenes like c-myc

Question 10

Loss of APC tumor suppressor causes an ________

Answer 10

overexpression of the c-myc oncogene, resulting in cancer

Question 11

In Breast and ovarian cancers, there are two similar predisposing genes:

Answer 11

BRCA1 and BRCA2

Question 12

About _____% of woman with breast cancers have inherited mutations in the BRCA1 or 2 genes.

Answer 12

5%

Question 13

Inherited cases of BRCA1/2 mutation display _____.

Answer 13

LOH and have only mutant BRCA1 or 2 genes

Question 14

In the acquired cases of BRCA1/2, the situation is different from that seen for RB in that _______.

Answer 14

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.

Question 15

Both BRCA1 and BRCA2 _________ may give rise to the many mutations needed for full-blown malignancy.

Answer 15

function in DNA repair and their loss

Question 16

BRCA2 has been shown to be allelic with________. This means that individuals with homozygous mutations in BRCA2 get _______, while heterozygotes get ______

Answer 16

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.

Question 17

mutant p53 is found in about __% of all cancers

Answer 17

50%

Question 18

p53 is a ______.

It also is important for the response of cells to environmental mutagenesis.

Answer 18

tumor suppressor gene.

response of cells to environmental mutagenesis

Question 19

Cells missing p53 accumulate ________.

Answer 19

mutations at a muchhigher rate and thereby, have a greater chance of becoming malignant

Question 20

p53 as a guardian of the genome

Answer 20

preventing potentially deleterious mutations.

In p53 defective cells, damaged DNA is replicated, thereby producing additional mutations including chromosomal rearrangements, which can lead to cancer

Question 21

The p53 gene was initially found to be an _________.

Answer 21

oncogene, in that certain p53 mutant genes were dominant to the wild-type gene in producing cellular transformation

Question 22

p53 acts as a classic tumor suppressor in _____

How?

Answer 22

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”.

Question 23

p53 protein acts as a transcription factor important for the expression of genes, which prevent cells from

Answer 23

from replicating damaged or foreign DNA

Question 24

_____is also required for apoptosis, in which cells commit suicide if their DNA is damaged beyond repair.

Answer 24

p53

Question 25

p53 “hotspots”.

Answer 25

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.

Question 26

an alteration in amino-acid 157 of p53 is found mainly in

Answer 26

lung cancer and is the result of the mutagenic chemicals found in cigarette smoke

Question 27

p53 interferes with the life cycle of many human viruses including ______.

Answer 27

Adenovirus and HPV (human papilloma virus)

Question 28

The viruses have oncogenes that act by ______,

examples:

Answer 28

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.

Question 29

APC is part of a protein complex that binds ______

Answer 29

beta-catenin in the cytoplasm

Question 30

Normally, beta-catenin is either _______.

Answer 30

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

Question 31

In the absence of normal APC, beta-catenin is ________

Answer 31

free to translocate into the nucleus and activate transcription factors on oncogenes (such as c-myc) without regulation by Wnt signaling.

Question 32

APC is functioning as a tumor suppressor by ________.

Answer 32

inhibiting the activation of oncogenic transcription factors by beta-catenin

Question 33

Loss of APC is found in patients with ______

Answer 33

Familial Adenomatous Polyposis (FAP).

Question 34

BRCA1 and BRCA2 function to ________.

Answer 34

suppress uncontrolled cell proliferation by repairing damaged DNA.

Question 35

The BRCA1 protein is a scaffold for protein complexes involved in _______

Answer 35

various DNA checkpoints. BRCA2 binds Rad51 and repairs double strand breaks.

Question 36

The ability of a mutated p53 gene to show dominance over the wild-type allele is due to a ________

Answer 36

dominant-negative effect

Question 37

dominant-negative effect of p53:

Answer 37

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.

Question 38

p53 acts as a transcription factor to ______.

Answer 38

inhibit replication of damaged DNA

Question 39

When damaged DNA is detected at DNA checkpoints, p53 ______.

Answer 39

induces apoptosis or cell cycle arrest

Question 40

Cell cycle arrest is achieved through _______

Answer 40

multiple pathways, which prevent the cell from entering into the S or M phase of the cell cycle until the DNA is repaired.

Question 41

Certain viruses make proteins that specifically target Rb and p53 to ________.
These proteins either _________.

Answer 41

disrupt their ability to effectively suppress tumor formation

inactivate Rb and p53 or target them for degradation

Question 42

Adenovirus, makes proteins E1A and E1B which target:

Answer 42

E1A: Rb
E1B: p53

Question 43

Human papilloma virus is an ___________

Answer 43

oncogenic virus in that it produces proteins that disrupt the activity of the tumor suppressors Rb and p53.

Question 44

HPV protein E7 binds to ________.

Answer 44

binds to and inactivates Rb, which pushes the cell to move forward through the cell cycle.

Question 45

HPV protein E6 function

Answer 45

ubiquitinates p53, targeting it for degradation.