HC2 - Viruses, oncogenes & growth factors Flashcards
cancer as infectious disease
until late 19th century, Rous sacroma virus (RSV)
virus
genetic material encapsulatedv
viruses and cancer
viruses can transform infected cells in culture
formation of foci
loss of contact inhibition
permissive host
allow virus replication and are killed quickly
non-permissive host
does not allow virus replication and causes transformation
intergration of viral DNA into host genome
- exploit replication machinery
HPV
99.7% of cervical carcinomas
episomal virus
outside of host genome, hitchhike during mitosis
retrovirus
reverse transcription to intergrate genetic material
kidnapping and exploiting host genes
v-src and c-src
existing normal genes
can be oncogenic
a single gene
sufficient for oncogenic transformation
virus vector
to deliver foreign DNA
kidnapped genes
most are silent, over 30 proto-oncogenes
induction of transformation
viral intergration next to proto-oncogene c-myc
insertional mutagenesis (mechanism c-myc)
strong viral promotor forces overexpression of c-myc gene > uncontrolable cell proliferation
viruses as carcinogenes
in 20% of cancers, HPV, Hep. B and C
not all cancers caused by virusses
- cancers don’t propagrate between humans
- no outbreaks
- non-biological reagents can be carcinogenic > chemicals and radiation
latent viruses
inactive proviruses can be reactivated by some chemicals > BrdU
mutations as drivers for transformation
- transfection of foreign DNA to test oncogenic potential of genes
- oncogens act across species = evolutionary conserved
cellular oncogenes
- often amplified in cancers
- multiple copies > increased protein production
HER2 in 30% of breast cancers
correlated with poor patient prognosis
tumor suppressor genes
counteract oncogenic transformation
deletion or mutation tumor suppressor genes
releases breaks on cell proliferation
proto-oncogenes
activated by genetic changes affecting protein expression or structure
H-ras bladder carcinoma oncogene
identical in length to normal human DNA, somatic point mutation
Burkitt’s lymphoma
-chromosome translocation fusing regions of chromosomes 2, 14, 22 to a region of chromosome 8
- places myc proto-oncogene under control of transcriptional activators of immunoglobulines
epidermal growth factor receptors (EGFR)
recognizes EGF and initiates intracellular signaling to promote growth
trunction EGFR
- in some carcinomas and glioblastomas
- lacks extracellular domain > sends growth-stimulatory signals even in absence of EGF
hybrid proteins in chronic myelogenous leukemia (CML)
abl proto-oncogene kinase (ch. 9) fuses with bcr region (ch 22.) > deregulation of abl protein > emits strong growth-promoting signals
MLL1 (ALL1) gene
- histone methylase participates in >50 fusions
- affects chromatin structure and function
different mechanisms for transformation
- changes in proto-oncogene expression level - changes in proto-oncogene structure
- complex cellular control systems
changes in proto-oncogene expression levels
- amplification
- insertional mutagenesis = control by an external promotor
- translocation = control by an active promotor of another gene
changes in proto-oncogene structure
- truncation
- hybrid protein
- mutation
complex cellular control systems
regulating levels of proteins posttranscriptionally
coordination of cell behavior
growth-stimulatory signals from their environment
cell membrane
barrier in cell transduction
growth factors (GF)
- convey signals between cells in a tissue
- dimerization and transphosphorylation
cancer alters growth factor metabolism
- overexpression or change of receptors
- enhanced autocrine signaling
EGFR amplication glioblastomas
increased levels of receptors can trigger activation
membrane-permeable ligands (small, hydrophobic)
- steroid sex hormones, retinoids, vitamin D
- bind directly to nuclear recpetor
