Carcinogenesis III Flashcards
Viral genome
gag gene: encodes internal virion proteins. Env gene for virus membrane glycoproteins. Pol gene for virus polymerase. (normally just reverse transcriptase, polymerase RNA –> DNA, integrate into host. This is retrovirus). So it gets transcribed, make more virus, translated into env, capsid, reverse transcrip… bam new virus GTG.
Mechanism and examples of v-onc
V-src (protein kinase), v-erb (encodes protein similar to EGFR), v-abl (protein kinase), v-myc.
Mechanism: when virus leaves it can take part of our genes (like sarc). we have a c-onc it becomes v-sarc.
Virus is integrated into DNA near c-sarc and aberrant trx event produces a hybrid RNA. v-onc often has mutations.
Retrovirus
single strand RNA containing membrane enclosed viruses that bud from cell mem of infected cells (don’t usually kill host cell).
How does v-onc cause neoplastic transformation?
Products of oncogenes mimic hormones or GF by resembling natural hormones or affecting structure of cell surface receptors for these hormones.
Altered receptors send signals to cell nucleus in unreg. manner to affect growth.
Mutants activating protein kinase without GF. Protein kinase constitutively active.
Quality vs. Quantity of oncogene
Quantity: wild-type but too much
Quality: present at normal level but has mutation and is too active (like GF indep. activation). (c-ras)
Both in cancer…
Example of oncogene fx?
V-abl codes for a protein kinase that phosphorylates tyrosine residues on other proteins. It is similar to human c-ABL (found in BCR-ABL translocation in philadelphia chromo and overexpressed in BCR-ABL CML).
Proto-oncogenes. C-onc.
Id’ed for their similarity to probes for v-onc. Also id’ed with transfection of DNA from human tumor cells in mammalian cell culture to produce malignancy.
Involved in spontaneous malignancies that have nothing to do with retrovirus.
Change in gene reg or structure b/c of mutation could activate these genes and cause malignancy (qualitative or quant).
C-onc properties
If v-onc originate from c-onc substantial rearrangements may have occurred (ex diff introns etc.).
Some c-onc genes ligated to retroviral promoters can transform normal cells when introducted via DNA mediated transformation (c-ras), others don’t transform normal cells. C-ras is qualitative, ras protein unreg and always “on”
Gene ampliciation of c-onc genes in some cancers (like n-myc in neuroblastoma). Her2 in rbeast.
Translocations of c-onc genes seen in some cancers.
Therapy for oncogenes
- ) Antibody that inhibits GF (Ab binds GFR and prevents it from working)
- ) Small mlc goes inside cell and inhibits activity of GFR (like tyrosine kinase).
Herceptin
antibody against HER2 (ERB2), which is overexpressed in breast cancer, seen w/ PCR.
Antibody binds this receptor and inhibits it. Humanized mab, increases efficacy of radiation (even in pts who had failed therapy, got better efficacy).
Gleevac
CML leukemia.
pts have too much ABL kinase, has active site and protein that is destined to get phosphorylated inds here, kinase tranfser high energy gamma phosphate from ATP and put it on protein to activate or inhibit it.
Gleevac out-competes ATP, binds pocket of ABL that’s unique so don’t affect other cells.
90% effective.
but 5 or 6 yrs later get resistance. Threonine allows ATP/drug to bind tightly (it gets changed to leucine in resistant pts, leucine is bigger, drug can’t bind). so now we use combo therapy to prevent resistance.
Heat map
Gene copy. used in cancer. Hybridize tumor DNA to “gene chip” w/ all human genomic DNA seq. as molecular probes.
Red= increase, green=- decrease.
Correlate molecular data with clinical info.
Personalized therapy & breast cancer
p53- poor prognosis, diagnosis (primary or secondary), therapy? ERB2 positive, herceptin treatment. High ER, tamoxifen.
Oncogene discovery?
in oncogenic retroviruses.
With a particular viral gene seg (v-onc) tumors rapidly induced in infected cells they grow on agar…
