B2.032 Oncogenes and Tumor Suppressor Genes

Question 1

what is an oncogene?

Answer 1

genes that promote autonomous cell growth

Question 2

what are proto-oncogenes?q

Answer 2

normal cellular counterpart of oncogenes

oncogene-mutation

Question 3

how does an oncoprotein differ from a normal protein?

Answer 3

quantity, quality, or function

Question 4

what are the classes of oncogenes?

Answer 4

growth factor
growth factor receptors
signal transduction proteins
nuclear regulatory proteins (transcription factors)
cell cycle regulators

Question 5

how do growth factor oncogenes work?

Answer 5

factors can be produced by cancer cells and set up in local autocrine or paracrine loops (not usually systemic growth factors, very localized to tumor)

Question 6

what type of activity do growth factor receptors have?

Answer 6

tyrosine kinase activity

Question 7

what is tyrosine kinase activity?

Answer 7

tyrosine kinase’s work to turn cellular functions “on” and “off” by phosphorylating proteins

Question 8

what is the primary growth factor receptor discussed?

Answer 8

ERB-B2 (HER-2/neu)

Human epidermal growth factor receptor 2

Question 9

what is the mechanism of HER-2/neu dysfunction?

Answer 9

amplified or overexpressed, stimulating cell growth and division

Question 10

what type of outcomes are associated with HER-2 amplifications in breast cancer?

Answer 10

poor clinical outcomes in cases w metastasis in lymph nodes

Question 11

what therapy was developed against HER-2 amplification?

Answer 11

trastuzumab (Herceptin)
monoclonal antibodies
first monoclonal antibody ever used in treatment of a solid organ malignant neoplasm

Question 12

why can you see HER-2 dysfunction on a slide?

Answer 12

HER-2 is overexpressed so there are multiple copies

fluorescence is brighter and staining is darker

Question 13

what are some examples of signal transduction proteins that can act as oncogenes?

Answer 13

GTP-binding proteins (G proteins)
nonreceptor tyrosine kinases
RAS
NOTCH
JAK/STAT

Question 14

what is the most common abnormality of oncogenes in human cancer?

Answer 14

G-protein pathway activations by RAS point mutations

Question 15

describe the G-protein oncogene pathway

Answer 15

RAS gets activated when a growth factor receptor bind to a growth factor
Activation of RAS allows for production of GTP
GTP later gets hydrolyzed to GDP by an autocatalytic reaction
if the autocatalytic reaction is inhibited, RAS stays active

Question 16

what proteins does active RAS stimulate, and what is the result?

Answer 16

RAF and PI3K directly
eventually D cyclin and MYC
cell growth

Question 17

what is an example of a nonreceptor tyrosine kinase oncogene?

Answer 17

activation of ABL by BCR/ABL translocation
ABL becomes activate when put next to BCR
stimulates proliferation

Question 18

what kind of protein is produced when BCR/ABL are fused?

Answer 18

chimeric protein

Question 19

how is chimeric protein detected?

Answer 19

yellow on a FISH scan

Question 20

what are two types of nuclear regulatory protein oncogenes?

Answer 20

C-MYC

N-MYC

Question 21

what is the mechanism of C-MYC oncogene activity?

Answer 21

overexpressed in B lymphocytes due to translocation next to immunoglobulin gene that is always on
Burkitt lymphoma

Question 22

what is the mechanism of N-MYC oncogene activity?

Answer 22

gene amplification

can be seen on karyotype as a HSR (homogenously staining region) or double minute fragments

Question 23

how do cell cycle regulators function as oncogenes?

Answer 23

shepherd cells through division, overexpression increases divsion

Question 24

how many alleles have to be inactivated on a tumor suppressor gene to have an effect?

Answer 24

both

Question 25

what are the primary tumor suppressor genes discussed?

Answer 25

TP53
Rb
APC

Question 26

how does normal Rb protein function?

Answer 26

inhibits transcription by binding transcription factor E2F
releases E2F when phosphorylated by cyclin/CDK complex
allows G1/S phase transition

Question 27

how can Rb be suppressed?

Answer 27

inactivation by products of oncogenic DNA virus (E6 and E7 of HPV)
loss of RB altogether

Question 28

what is the most common genetic defect in human neoplasms?

Answer 28

TP53

Question 29

how does the normal p53 pathway function?

Answer 29

upregulated by DNA damage, stress, etc.

accumulation of p53 leads to cell cycle arrest or activation of genes involved in DNA repair

Question 30

how can the normal p53 pathway be inactivated?

Answer 30

inactivating mutations in TP53
abnormal regulation of p53 activity
inactivation of p53 protein by produces of oncogenic DNA viruses

Question 31

how do tumors with TP53 mutations respond to treatment?

Answer 31

relatively resistant

no ability to recognize DNA damage

Question 32

how does normal APC function?

Answer 32

binds and inhibits B caterin, prevents activation of transcription factors by B caterin