Carcinogenesis III Flashcards
Oncogenes were discovered in ______
certain oncogenic retroviruses.
Retroviruses are
RNA containing membrane enclosed viruses that bud from the cell membrane of infected cells and which usually do not kill the infected cell.
The RNA genome consists of _________
two identical strands held together by a tRNA molecule.
The gag gene codes for
internal virion proteins
When gag genes are the only ones present, the virus does not ______, but _______.
cause tumors
replicates through an intermediate proviral DNA and integrates into the host cell genome
Virus can be transmitted as an _______
integrated provirus through somatic or sex cells as a cellular gene.
Retroviruses that contain a v-onc segment also have the ability to _______
rapidly transform appropriate infected cells to the malignant phenotype. They therefore rapidly induce tumors after infection.
examples of retrovirus with v-onc segments
- v-src
- v-erb
- v-abl
- v-myc
v-src -
v-src - The oncogene of Rous Sarcoma Virus. This caused fibrosarcomas in certain birds.
v-erb
v-erb - The oncogene of avian erythroblastosis virus causes erythroblastosis in chickens. Two related genes, erb-A and erb-B have been identified.
v-abl -
v-abl - The oncogene found in Abelson leukemia virus from mice.
v-myc -
v-myc - This gene is usually fused with a portion of the gag gene. It appears that this gene is capable of eliciting neoplastic transformation of cells.
Cellular Transformation is assayed by:
a. Tumor formation in animals after administration of the oncogenic virus.
b. Transformation of cell morphology and growth regulation after infection of cultured cells in vitro. Foci of infected cells developing as transformed clones can be seen and counted
The protein (pp60v-src) coded by the v-src gene is a \_\_\_\_\_\_\_\_\_. Theses proteins then change the properties of the cells by affecting \_\_\_\_\_.
membrane bound protein kinase that phosphorylates tyrosine residues in several different proteins.
gene expression
v-erb-B codes ________.
codes for a protein that is similar in structure to the cell surface receptor for epidermal growth factor (EGFR).
This raises the possibility that this protein has growth stimulating properties like EGFR.
EGFR receptor is a member of a family of related proteins that _______
(like pp60v-src) exhibit tyrosine-specific protein kinase activity
v-abl codes for a _______.
protein kinase that phosphorylates tyrosine residues on other proteins
v-able is similar to the human cellular gene (c-ABL) that is found in the______
BCR-ABL translocation in the Philadelphia chromosome and is overexpressed in BCR-ABL CML
Many of the products of oncogenes mimic _______
hormones or growth stimulating factors either by resembling natural hormones or by affecting the structure of the cell surface receptors for these hormones
oncogene altered receptors then send signals to the ________
cell nucleus in an unregulated manner to affect growth.
c-onc genes
Proto-oncogenes
Cellular prototypes of the v-onc genes exist in_______ .
all normal eukaryotic cells
The proto-onc or c-onc genes are involved in _______
spontaneous malignancies that have nothing to do with a retrovirus.
a change in gene regulation or gene structure due to a cellular mutation could _______
activate these genes to cause a malignancy.
quantitative changes (too much protein) or qualitative changes (overactive or unregulated protein) in the proto-oncogene are responsible for these effects.
quantitative changes
too much protein
qualitative changes
overactive or unregulated protein
c-src has a differences from v-src
different carboxy-terminal amino acid sequence
and c-src has numerous introns that do not exist in v-src.
c-myc differences than v-myc
c-myc also has many introns not present in v-myc, although the coding sequences are nearly identical (7 amino acid changes)
if v-onc genes originated from c-onc genes, substantial rearrangements occurred _____
during or after the capture (at least with many such oncogenes).
A few c-onc genes ligated to retroviral promoters can _________
transform normal cells when introduced via DNA mediated transformation (examples: c-ras). Other c-onc genes do not directly transform normal cells.
c-ras genes have been ______,
point mutated
Mutations are found in either codon 12 or codon 61 of the ras gene product.
c-ras point mutations produce a _____
ras protein that is unregulated and is always “on”. Detection of these ras mutations indicates a poor prognosis.
Gene amplification of c-onc genes has also been detected in some ______.
cancers and is very useful for prognosis.
N-myc, a member of the______, and is found ______.
c-myc family of oncogenes
amplified in neuroblastoma
The HER2/neu oncogene (also called erbB2), which encodes a ________.
integral membrane protein kinase (see v-erb-B) is amplified in about 20% of breast cancers.
Higher levels of amplification correlate with a poor prognosis.
support for the quantitative model
HER2/neu being amplified in breast cancer
support for qualitative model:
c-ras genes being point mutated and always on
Translocations of c-onc genes have been observed in certain human cancers, and also indicate ______.
a poor prognosis
The translocation results in
inappropriate and high level expression of the oncogene (See Burkitt lymphoma and the Philadelphia chromosome (BCR- ABL translocation)
several genes must _________. to transform a normal cell to a malignant one
simultaneously be changed to transform a normal cell to a malignant one.
Mutations in both tumor suppressors and oncogenes are needed.
The best evidence for this idea has been found in colon cancer.
loss of _____ and an increased ______ coupled to loss of _____ can be particularly deadly.
growth regulation
mutation rate
programmed cell death (apoptosis)
In theory, tumor cells may have some of their properties reversed by either _________. This can be accomplished either __________
blocking the action of oncogenes and/or adding back any missing tumor suppressors.
at the gene level (gene therapy) or by using drugs or antibodies.
monoclonal antibodies specific for the protein product of the HER2/neu/erbB2 oncogene can ______. These antibodies are called _____
HER2/neu/erbB2 oncogene can reverse the transformed phenotype of the cancer cell
V
drugs that inhibit HER2/neu/erbB2 are being used to ______
extend the life of breast cancer patients. More drugs of this type are currently in clinical trials for both breast and lung cancer.
Injection of the RB gene into a RB-negative small cell lung cancer line will inhibit _____.
tumorigenesis.
E1B mutant adenoviruses:
which cannot inactivate p53 and thereby cannot kill wild-type cells, will kill p53- cancer cells preferentially
A drug has been used to correct the mutant conformation of dominant-negative p53 mutations . This drug blocks the _______
production of tumors by these p53 mutant cells in a mouse model system.
In patients with BCR-ABL translocation, the ABL tyrosine kinase can be inhibited by
Gleevac, an ATP analogue. Clinical trials have shown that
Gleevac is effective in 95% of these patients
“Molecularly targeted therapy” or “rationally designed drug therapy.”
identifying the defect in the tumor from the patient and then targeting the therapy to fit it.
Why do drugs that inhibit “normal” cellular proteins (c-myc, c-abl, etc.) kill only the cancer cells?
One idea is that cancer cells but not normal cells have become dependent or “addicted” to the overexpressed oncogene.
This referred to as “oncogene addiction”
oncogenes and tumor suppressor genes are being used as “molecular markers” in both ____
cancer diagnosis and prognosis.
The elucidation of the function of these genes also will be useful for therapies, either at the gene and/or protein levels and forms the basis of _______
“Personalized Medicine”.
_________ is being used for targeted therapy and for “personalized medicine” in cancer.
Molecular knowledge of the genome in cancer cells (Bioinformatics)
“heat map” is created in which changes in gene copy number are _____. The “heat map” is created by ___________.
correlated with tumor grade
hybridization of the tumor DNA to “gene chip” containing all human genomic DNA sequences as molecular probes
Heat map, red color indicates:
green indicates:
Red color indicates increases and
green indicates decreases.
The Breast cancer Xpress ChipTM measures the expression of _____.
123 genes known to be altered in breast cancers
This includes tumor suppressors such as BRCA1 and p53 and oncogenes such as estrogen receptor (ER) and erbB2. The information is then used for diagnosis, prognosis and therapy.
patients with high erbB2 are treated with _____ and those with high ER levels are treated with ______
Herceptin
tamoxifen (estrogen antagonist).
With the advent of whole genome sequencing, cancer therapy is being designed _____
on a personal basis depending on the type of mutations (oncogene, tumor suppressor, etc.) in the tumor and the known therapeutic responses to these lesions
the env gene codes for
for virus membrane glycoproteins,
pol gene codes for
a virus polymerase
