B2.032 Oncogenes and Tumor Suppressor Genes Flashcards
what is an oncogene?
genes that promote autonomous cell growth
what are proto-oncogenes?q
normal cellular counterpart of oncogenes
oncogene-mutation
how does an oncoprotein differ from a normal protein?
quantity, quality, or function
what are the classes of oncogenes?
growth factor growth factor receptors signal transduction proteins nuclear regulatory proteins (transcription factors) cell cycle regulators
how do growth factor oncogenes work?
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)
what type of activity do growth factor receptors have?
tyrosine kinase activity
what is tyrosine kinase activity?
tyrosine kinase’s work to turn cellular functions “on” and “off” by phosphorylating proteins
what is the primary growth factor receptor discussed?
ERB-B2 (HER-2/neu)
Human epidermal growth factor receptor 2
what is the mechanism of HER-2/neu dysfunction?
amplified or overexpressed, stimulating cell growth and division
what type of outcomes are associated with HER-2 amplifications in breast cancer?
poor clinical outcomes in cases w metastasis in lymph nodes
what therapy was developed against HER-2 amplification?
trastuzumab (Herceptin)
monoclonal antibodies
first monoclonal antibody ever used in treatment of a solid organ malignant neoplasm
why can you see HER-2 dysfunction on a slide?
HER-2 is overexpressed so there are multiple copies
fluorescence is brighter and staining is darker
what are some examples of signal transduction proteins that can act as oncogenes?
GTP-binding proteins (G proteins) nonreceptor tyrosine kinases RAS NOTCH JAK/STAT
what is the most common abnormality of oncogenes in human cancer?
G-protein pathway activations by RAS point mutations
describe the G-protein oncogene pathway
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
what proteins does active RAS stimulate, and what is the result?
RAF and PI3K directly
eventually D cyclin and MYC
cell growth
what is an example of a nonreceptor tyrosine kinase oncogene?
activation of ABL by BCR/ABL translocation
ABL becomes activate when put next to BCR
stimulates proliferation
what kind of protein is produced when BCR/ABL are fused?
chimeric protein
how is chimeric protein detected?
yellow on a FISH scan
what are two types of nuclear regulatory protein oncogenes?
C-MYC
N-MYC
what is the mechanism of C-MYC oncogene activity?
overexpressed in B lymphocytes due to translocation next to immunoglobulin gene that is always on
Burkitt lymphoma
what is the mechanism of N-MYC oncogene activity?
gene amplification
can be seen on karyotype as a HSR (homogenously staining region) or double minute fragments
how do cell cycle regulators function as oncogenes?
shepherd cells through division, overexpression increases divsion
how many alleles have to be inactivated on a tumor suppressor gene to have an effect?
both
what are the primary tumor suppressor genes discussed?
TP53
Rb
APC
how does normal Rb protein function?
inhibits transcription by binding transcription factor E2F
releases E2F when phosphorylated by cyclin/CDK complex
allows G1/S phase transition
how can Rb be suppressed?
inactivation by products of oncogenic DNA virus (E6 and E7 of HPV)
loss of RB altogether
what is the most common genetic defect in human neoplasms?
TP53
how does the normal p53 pathway function?
upregulated by DNA damage, stress, etc.
accumulation of p53 leads to cell cycle arrest or activation of genes involved in DNA repair
how can the normal p53 pathway be inactivated?
inactivating mutations in TP53
abnormal regulation of p53 activity
inactivation of p53 protein by produces of oncogenic DNA viruses
how do tumors with TP53 mutations respond to treatment?
relatively resistant
no ability to recognize DNA damage
how does normal APC function?
binds and inhibits B caterin, prevents activation of transcription factors by B caterin
