082614 molecular oncogenesis Flashcards
cancer gene targets are?
protooncogenes (activation) tumor supp. genes antiapoptosis genes apoptosis genes DNA repair genes
protooncogene
normal regulatory gene of cell growth
encodes proteins that are growth factors, growth factor receptors, singal transducers, transcription factors, cell-cycle regulators
tight regulatory control
oncogene
protooncogene that’s altered
genes involved in autonomous, unregulated cell proliferation
constitutively expressed
how can growth factor receptors play a role in cancer?
normally they are transiently activated, leading to dimerization and tyrosine phosphyrltation
can have abnormal constitutive activation–overexpression or mutations
ex of growth factor receptors that are encoded by oncogenes
ERB B2 gene (HER2/Neu)
c-KIT gene
how does targeted drug therapy target ERB B2 growth factor receptor amplification in breast cancer?
herceptin attaches cancer cell with receptor and tells immune system to target the cancer cell
also, herceptin can stop the cancer from sending to itself signals to grow and divide
how to target c-KIT mutations in cancer?
c-KIT is a growth hormone receptor
can use a tyrosine kinase inhibitor
what is the single most common abnormality of oncogenes in tumors?
point mutation in RAS
what mechanism is reduced in the point mutation of RAS?
GTPase activity
c-ABL gene
encodes signal transducing protein that is not receptor linked
protein has tyrosine kinase activity that is normally TRANSIENT
what is the philadelphia chromosome?
abnormality in chromosome associated with chronic myelogneous leukemia and acute lymphoblastic leukemia
due to abl gene translocation from chromosome 9 to 22, which renders its expression constitutive
myc oncogene
encodes a transcription factor
normally as protooncogene would have transient increase in expression
the oncogene has mutated forms that lead to continued expression (c-myc) or amplification (numberous gene copies: n-myc)
how does c-MYC play a role in Burkitt lykmphoma?
the gene translocates from chromosome 8 to 14, causing it to be constitutively turned on because it is now located by the heavy Ig chain gene
how does n-MYC gene play a role in disease?
it gets amplified in neuroblastoma
how is cyclin D1 involved in tumorgenesis?
is overexpressed in mantle cell lymphoma
due to translocation from chromosome 11 to 14, the Ig heavy chain locus
if cyclin D overexpressed, will cause activation of CDKs and phosphorylation of Rb protein which will cause cell cycle to keep going
Two hit hypothesis
loss of fxn of something like tumor suppressor gene would need mutations in both alleles for oncogenesis
RB gene
encodes a tumor suppressor protein that is a cell cycle regulator
mutations in RB cause failure of E2F regulation, so you get uncontrolled E2F activation and unregulated cell growth, leading to retinoblastoma
APC gene
gene involved in destruction of beta-catenin
tumor suppressor gene
if mutated (two hits), beta catenin accumulates and complexes with TCF, a transcription factor, to stimulate growth factor transcription
APC gene disease ex
familial adenomatous polyposis-APC mutations
p53
tumor suppressor gene
function normally is to, after DNA damage, arrest the cell in the cell cycle or repair DNA or initiate apoptosis
ex pf p53 gene disease
Li-Fraumeni syndrome-inherit a mutated p53 allele (tumor suppressor gene)
increased risk of developing cancer by age 50
5 types of protooncogenes
growth factors growth factor receptors signal transducers transcription factors cell-cycle regulators
what is an ex of pro-apoptotic protein?
Bax
ex of anti-apoptotic protein?
Bcl-2
how does BCL-2 play a role in oncogenesis?
prevents cells from apoptosis
t(14;18) in follicular lymphoma; get overexpression (this is a lower grade tumor b/c it’s not to die vs being told to grow
types of specific DNA alterations in cancer
see slide with table
what are direct and indirect acting carcinogens
direct: highly reactive electron deficient compounds that react with DNA, RNA, protein (don’t require processing)
indirect: metabolized by cytochrome P450 system
initiator vs promoter compounds
initiator is a CHEMICAL that causes permanent DNA mutations (includes direct and indirect acting)
promoter is a nontumorigenic chemical that boosts the proliferation of mutated cells (REVERSIBLE effect), with examples such as hormones and alcohol
polycyclic aromatic hydrocarbons’ role in lung cancer, bladder cancer, and laryngeal cancer
found in tobacco smoke, combustion of coal
is an INITIATOR
how do viruses cause oncogenesis
viral genome integrates into host DNA–can get overexpression of viral proteins that affect host cell growth or disruption of protooncogene
can stimulate host inflammatory response with subsequent regeneration, which has the potential for insults to DNA and tumorgenesis
how can EBV infection contribute to Burkitt lymphoma?
in an immunosuppressed pt, there’s lack of T cells regulating B cells so B cells proliferate and aren’t checked
how do hepatitis viruses cause oncogenesis
chronic liver injury leads to regeneration
HBx protein of hep B activates growth genes and inhibits p53
how does H. pylori cause oncogenesis
host inflammatory response contributes to carcinogenesis(regeneration, metaplasia, dysplasia, carcinoma)
polycloncal expansion of lymphocytes in MALT can select for clonal population with additional mutations (extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue)
