Intro to Cancer Exam 2 Study Questions

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1. What is an cellular oncogene?: -a cell that has the potential to cause cancer
-in tumor cells, they are expressed in high levels
-activated from proto-oncogenes by mutation or transcriptional activation
2. What is a proto-oncogene?: A normal gene that can become an oncogene
due to mutations or increased expression
3. Describe two examples of molecular mechanisms by which a proto-onco-
gene has been converted to an oncogene.: Mutation-causes gene to become
permanently activation-affecting structure of protein or transforming oncoprotein
(MAP kinase (mitogen activated protein kinase) code for the proteins that affect
mitosis, inflammatory cytokines production, cell differentiation etc.)--can cause
TSGs to develop

Point mutation- G replaced w T and changes oncoproteins-Hras gene-causes

structural change and inc exp pf gene

gene amplification- involves the increase of copy no. of genes which are involved in
cell division and prolif-. Some studies also gave the idea that the no. of genes are
also increased in tumor conditions which are involved in inhibition of cell division
regulatory proteins. Amplification of genes enhances the rate of cell divison and
increase tumor formation.
Example: double-minute chromosomes (DMs) and homogeneous staining regions
(HSRs).
Several research gave the idea that approximately 15% to 30% of breast and
ovarian cancers have amplification of the erbB-2 (HER-2/neu) gene.

translocation of chromosomes- fusion from one chromo to non homologous chro-

mo-places gene under control of foreign transcription factor promotor which leads
to over expression -translocation may free mRNA from inhibition by a microRNA
by removing mRNA sequences normally recognized by miRNA
- can result in fusion of 2 protein coding sequences to form hybrid protein
(BCR-ABL proteins in CML cancer)

truncation- of EGF receptor causes protein to emit growth promoting sigs

4. If you were given a piece of cellular DNA, describe an experiment to
determine if it contains an oncogene? What results of the experiment would
suggest that the DNA was an oncogene, and what results would suggest that
it was not an oncogene?: Transfection

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DNA from chemically transformed cells introduced into normal cells --> recipient
cells monitored to see if they were transformed

transformed cells
-led to tumor
-anchorage independent
-carried genes that are oncogenes
-contains properties of oncogenes: cell proliferation inc gene expression, muta-
tions, translocation, gene amplification
5. What is a growth factor?: a protein released by certain cells that stimulates
other cells to proliferate, grow, and divide

influence normal celldifferentiation, and constitutive activation of growth-promoting

pathways

in cancer cells GF is not needed, and cells proliferate on their own

transformed mesenchymal cells produce PDGF (the product of the c-sis pro-
to-oncogene) and certain transformed cells both produce and respond in a
growth-stimulatory manner to TGF².With TGF²,which is a growth inhibitor for certain
epithelial and other cell types, the loss of the normal inhibitory response in trans-
formed cells could have the same result as the activation of a growth-stimulatory
response.
6. What is a receptor?: protein that detects a signal molecule and performs an
action in response

G-protein-coupled receptors (GPCRs) comprise a large family of cell-surface

receptors that regulate many cell functions, including cell proliferation, survival and
motility, and have recently emerged as key players in tumour growth, angiogenesis
and metastasis.

tumor cell proliferation is regulated by many neuropeptides, PGE2, thrombin, S1P,

LPA and IL8, which signal through their cognate receptors to stimulate G± s, G±
i, G±
q
and G±12thereby initiating the activity of a signaling network that includes sec-
ond-messenger-generating systems, small GTPases of the Ras and Rho families,
and mitogen-activated protein kinase (MAPK) cascades that regulate the nuclear
expression of growth-promoting genes.

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7. What is a receptor ligand?: a molecule which produces a signal by binding to
a site on a target protein

nonapoptotic and tumor-promoting activities. CD95 and CD95L were discovered to

be critical survival factors for cancer cells, and were found to protect and promote
cancer stem cells

CD95 is a surface receptor that has the capacity to mediate apoptosis induction in
cancer cells.
8. What are cell responses to growth factors activating their receptor?

How are normal receptors altered to become onco-protein receptors?: -

Growth factor activation of receptor tyrosine kinases (RTKs) provokes well-de-
scribed canonical second messenger pathways that transmit biochemical signals
in the cytoplasm and to the nucleus to initiate cellular responses.

Tk attaches phosphates to tyrosine residues of proteins

tyrosine phosphorylation is favored by mitogenic signaling pathways

ex: EGF-R
-binding of GF-ligand to N-terminal ectodomain induces dimerization of the recep-
tor
-this activates each monomers kinase to phosphorylate its partners tyrosine on the
partner's C-terminal cytoplasmic domain
-resulting phosphotyrosines enable emission of mitogenic signals downstream
target protein within cells
9. Why is signal transduction sometimes referred to as a cascade?: a series
of chemical reactions which are initiated by a stimulus (first messenger) acting on a
receptor that is transduced to the cell interior through second messengers (which
amplify the initial signal) and ultimately to effector molecules, resulting in a cell
response to the initial stimulus.

At each step of the signaling cascade, various controlling factors are involved
to regulate cellular actions, responding effectively to cues about their changing
internal and external environments
10. The src oncoprotein functions in the signal transduction pathway as
which of the following?
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A.Growth factor ligand

B.Cell surface receptor
C.Kinase enzyme
D.Nuclear transcription factor
E.All of the above: C - kinase enzyme
11. How does the epidermal growth factor receptor (EGF-R) signal to the
rasprotein that it has been activated by its ligand the epidermal growth
factor: -binding of GF-ligand to N-terminal ectodomain induces dimerization of the
receptor
-this activates each monomers kinase to phosphorylate its partners tyrosine on the
partner's C-terminal cytoplasmic domain
-resulting phosphotyrosines enable emission of mitogenic signals downstream
target protein within cells

(EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such

as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head
and neck cancer, pancreatic cancer, and breast cancer.

EGFR aberrations over-activate downstream pro-oncogenic signaling pathways,

including the RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways. These
pathways then activate many biological outputs that are beneficial to cancer cell
proliferation, including their chronic initiation and progression through the cell
cycle.

molecular mechanisms that regulate EGFR signal transduction, including the

EGFR structure and its mutations, ligand binding and EGFR dimerization, as well
as the signaling pathways that lead to G1 cell cycle progression. We focus on
the induction of CYCLIN D expression, CDK4/6 activation, and the repression of
cyclin-dependent kinase inhibitor proteins (CDKi) by EGFR signaling pathways.
12. How does the inactive rasprotein become active?: RAS= switch
Normally GDP-bound and inactive, Ras proteins are converted to the active,
GTP-bound conformation by guanine nucleotide exchange factors (GEFs), and
back again to the resting state by GTPase-activating proteins (GAPs) that stimulate
the intrinsic GTPase activity of Ras.

Ras hasan intrinsic GTPase activity, which means that the proteinon its own will
hydrolyze a bound GTP molecule into GDP.

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The Ras superfamily G-proteins interact at their effector domains with their down-
stream effectors via protein-protein interactions. Mutational activation or overex-
pression of the Ras superfamily G-proteins has been observed in a number of
human cancer cases.
13. What does it mean for the rasprotein to be active?: Ras is involved in the
signals passed between cells that control the amount of growth that is allowed
at any time. Cancer-causing mutation of Ras creates a form of the protein that is
ALWAYS ON
14. What are the three downstream pathways that are regulated by the
rasprotein?: THE MITOGEN ACTIVATED PROTEIN KINASE (MAPK) PATHWAY

THE PI3 KINASE PATHWAY

THE RAL PATHWAY

15. What are the biological consequences for each of the three pathways
downstream of the rasprotein?: THE MITOGEN ACTIVATED PROTEIN KINASE
(MAPK) PATHWAY
-no contact inhibited growth
-focus formation
-anchorage independent growth
-chromatin remodeling

THE PI3 KINASE PATHWAY

-normal endocrine-beta cells in the pancreatic islets are responsive to glucose
-constitutively active mutant Akt/PKB mutant cells grow to larger volumes
-bad inhibition of apoptosis
-stim cell growth and proliferation

THE RAL PATHWAY

-normal cell attaches to substrate
-mutant cells don't have to attach to substrate
-filopodia
-lamellipodia
16. Explain how melanoma cells may have an activated rasMAPK pathway
without a mutated rasprotein: In normal cells, the tightly regulated pathway
relays extracellular signals from cell membrane to nucleus via a cascade of
phosphorylation events.

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In the absence of RAS mutation, RAS activation can be aberrantly driven in
melanoma through the autocrine or paracrine hyperactivation of growth factor
receptors, such as c-Met, epidermal growth factor receptor and c-Kit

in melanomas lacking B-RAF or RAS mutations the signaling cascade is triggered

by other autocrine mechanisms including C-MET over expression, which is a re-
ceptor for hepatocyte growth factor, or through down regulation of MAPK pathway
inhibitory proteins such as RAF-1 inhibitory protein or SPRY-
17. The normal form of the rasprotein differs from the oncogenic form of the
rasprotein in which of the following ways?

A.The normal protein binds GTP but the oncogenic form does not.
B.The normal protein binds GDP but the oncogenic form does not.
C.The normal protein binds GEF but the oncogenic form dose not.
D.The normal protein binds GAP but the oncogenic form does not.
E.All of the above.: D
18. How do tumor suppressor genes (TSGs) differ from oncogenes?

An analogy to an oncogene is an accelerator in a car, and analogy to a tumor

suppressor gene is a break. Explain by this analogy how a tumor suppressor
gene can result in a tumor.: TSG differ from oncogenes in that they normally slow
down cell division or promote apoptosis.

Whereas protooncogenes become oncogenic when activated, tumor suppressor

genes promote malignant transformation when they are inactivated or deleted.

tumor suppressors, makes proteins that normally prevent cell division or cause cell
death. ...

Mutations that produce oncogenes accelerate growth while those that affect tumor
suppressors prevent the normal inhibition of growth.

TSG doesn't stop growth and cells turn to tumors when inactivated or deleted
19. What is meant by loss of heterozygosity(LOH)?: a specific type of genetic
mutation during which there is a loss of one normal copy of a gene or a group of
genes. ...

LOH of particular genes is associated with specific cancer types, such as such as
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colorectal cancer and small-cell lung cancer.

The gene might be completely gone, or part of it might have been moved to another
location on the DNA. In either case, the protein encoded by the gene cannot be
correctly made. Instead of having two different versions of the same gene present
(heterozygosity), one copy of the gene is now gone
20. By what genetic mechanisms can loss of heterozygosity occur?: can
be caused by direct deletion, deletion due to unbalanced rearrangements, gene
conversion, mitotic recombination, or loss of a chromosome (monsomy).
21. How can LOH by deletion facilitate cloning of a tumor suppressor gene?-
: Tumor suppressor genes can be inactivated by promoter silencing as a result of
methylation or dual inactivation by either mutation or a combination of mutation of
one allele and loss of the retained allele (LOH)

Following initial mutational inactivation or activation of one allele, the remaining

wild-type allele is deleted at the same time as the mutated allele is duplicated.

loss of genetic info and TSG function through genetic mutation or epigenetic
silencing via promotor methylation
22. What are examples of cancers resulting from mutations of TSGs?: ovar-
ian, lung, colorectal, head and neck, pancreatic, uterine, breast, and bladder
cancer.
23. What are examples of biochemical mechanisms by which mutant tumor
suppressor proteins result in tumors?: deletion and mutation
uncontrolled cell division

-mitotic recombination
-loss of chromo region that harbors the gene
-inappropriate chromo segregation (nondisjunction)
-gene conversion stemming from switch in template strand during replication

normally acting to inhibit cell proliferation and tumor development. In many tumors,
these genes are lost or inactivated, thereby removing negative regulators of cell
proliferation and contributing to the abnormal proliferation of tumor cells

LOH causes loss on ability to form hybrids and non-hybrids lead to tumors

In hereditary retinoblastoma, a defective copy of the Rb gene (Rb-) is inherited

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from the affected parent. A second somatic mutation, which inactivates the single
normal Rb+ copy in a retinal cell, then leads to the development of retinoblastoma.
In nonhereditary cases, two normal Rb+ genes are inherited, and retinoblastoma
develops only if two somatic mutations inactivate both copies of Rb in the same
cell.
24. Tumor suppressor mutations are recessive at the cellular level, but ap-
pear dominant in family patterns of inheritance. Explain: If only one allele for
the gene is damaged, the second can still produce the correct protein.

2 separate mutations required

defective gene inherited from parent

with LOH, there's no normal gene and mutant tumor suppressor alleles are
dominant.

retinoblastoma: hereditary cases often developed bilateral tumors and would de-
velop them earlier in life, compared to non-hereditary cases where individuals were
only affected by a single tumor.

However, affected parents could have children without the disease; but the unaf-
fected became parents of children with retinoblastoma.[4] This indicates that one
could inherit a mutated germ-line but not display the disease.
25. Select the one best choice.

A. A homozygous wild type tumor suppressor gene

can suppress a tumor.
B. A homozygous wild type tumor suppressor gene
cannot suppress a tumor.
C. A heterozygous wild type gene and mutant tumor suppressor gene can
suppress a tumor.
D. A heterozygous wild type gene and mutant tumor suppressor gene can
not suppress a tumor.
E. Statements A and C are True.: A,C
26. What does "cycle" refer to in the term "cell cycle"?: cycle of stages that
cells pass through to allow them to divide and produce new cells.

keeps going on an on and repeating

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specific process
27. What are the names of the phases of the cell cycle, and what are the
defining activities in each phase?: INTERPHASE:
*G1 phase
-Cell increases in size
-Cellular contents duplicated

*S phase
-DNA replication
-Each of the 46 chromosomes (23 pairs) is replicated by the cell

*G2 phase
-Cell prepares for cell division

M PHASE :
-Mitosis followed by Cytokinesis (cell separation)
-Formation of two identical daughter cells

*Prophase
-Nucleolus disintegrates
-Nuclear membrane breakdown
-Spindle fibres appear

*Prometaphase
-Spindle fibres attach to chromosomes
-Chromosomes condense

*Metaphase
-Chromosomes align at the metaphase plate

*Anaphase
-Centromeres divide
-Sister chromatids move to opposite poles

*Telophase
-Nuclear membrane reforms
-Chromosomes decondense
-Spindle fibres disappear
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*Cytokinesis
-involves a division of the cytoplasm
-considered a separate step to mitosis.
28. What is meant by cell cycle "restriction point" or "checkpoint". Give
examples.: check point that makes sure the previous stage was completed fully
and properly before the cell moves onto the next phase

makes sure the genes were not damaged or altered

point in G1 of the cell cycle at which the cell becomes "committed" to complete
the cell cycle or to remain in G1 & possibly retreat from active cell cycle to G0
phase(quiescent state)

deregulation if R point leads to cancer since it in uncontrolled cell proliferation

after passes R point, no longer active to extracellular signals and just proceeds
with cell cycle

EX:
-Damage to DNA and other external factors are evaluated at the G1 checkpoint; if
conditions are inadequate, the cell will not be allowed to continue to the S phase
of interphase.

-The G2 checkpoint ensures all of the chromosomes have been replicated and that
the replicated DNA is not damaged before cell enters mitosis.

-The M checkpoint determines whether all the sister chromatids are correctly at-
tached to the spindle microtubules before the cell enters the irreversible anaphase
stage.
29. Why are some proteins called "cyclins"? Give an example.: cyclin: any of
a group of proteins that regulates the cell cycle by forming a complex with kinases

Two groups of proteins, cyclins and cyclin-dependent kinases (Cdks), are respon-
sible for promoting the cell cycle.

Cyclins regulate the cell cycle only when they are bound to Cdks; to be fully active,
the Cdk/cyclin complex must be phosphorylated, which allows it to phosphorylate
other proteins that advance the cell cycle.
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cyclin D communicates with extracellular signals

30. What are cyclindependent kinases? Give an example of how one func-
tions in regulating cell cycle progression.: a member of a family of protein
kinases first discovered for its role in regulating the cell cycle through phospho-
rylation

Through phosphorylation, Cdks signal the cell that it is ready to pass into the
next stage of the cell cycle. As their name suggests, Cyclin-Dependent Protein
Kinasesare dependent on cyclins, another class of regulatory proteins. Cyclins
bind to Cdks, activating the Cdks to phosphorylate other molecules.
31. Give examples of positive and negative regulation of cell cycle pro-
gression.: In positive regulation, active molecules such as CDK/cyclin complexes
cause the cell cycle to progress.

In negative regulation, active molecules halt the cell cycle. The best understood
negative regulatory molecules are retinoblastoma protein (Rb), p53, and p21. ...
Rb, p53, and p21 act primarily at the G1 checkpoint.
32. How does the normal Rbprotein regulate cell cycle progression?: One
function of Rb is to prevent excessive cell growth by inhibiting cell cycle progression
until a cell is ready to divide. When the cell is ready to divide, Rb is phosphorylated
to pRb, leading to the inactivation of the activity of Retinoblastoma protein. This
process allows cells to enter into the cell cycle state.

It is a tumor suppressor protein that prevents excessive cell growth. If not mutated,
it is present in our cells and blocks the growth of dysfunctional cells between the
G1 and S phase of the cell cycle before they can undergo DNA replication.
33. Why is the gene that codes for the pRbprotein referred to as a
tumor suppressor gene?: The RB1 gene provides instructions for making a
protein called pRB.

This protein acts as a tumor suppressor, which means that it regulates cell growth
and keeps cells from dividing too fast or in an uncontrolled way.
34. DNA tumor viruses produce oncoproteins that function in which way?

A.The oncoproteins bind the E2F transcription factor, releasing restriction of

cell cycle progression restriction.
B.The oncoproteins bind the cyclin dependent kinase protein that phospho-
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rylate the Rbprotein.
C.The oncoproteins bind the Rbprotein that binds E2F transcription factor.
D.The oncoproteins bind the R restriction freeing it to allow cell cycle pro-
gression.
E.None of the above.: C

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