7 Molecular biology of Cancer Flashcards
What is cancer as a disease characterized by?
loss of regulation of the cell cycle
Cancerous cell bypass normal cell division checkpoints and allows defective DNA replication. What does this lead to a greater frequency of?
aneuploidy or a the incorrect number of chromosomes
describe in one word the division of cancerous cells
unregulated (NOT faster…)
what are the three usual sources of DNA mutations?
ionizing radiation(UV)
chemicals
spontaneous errors during replication
what are the two outcomes that can result if a mutation is detected by the cell?
corrections can be made and resume normal cell proccess
if mutation is severe or numerous enough –> apoptosis
what are four diseases that is due to defects in DNA repair and what are their phenotypes as well as the process affected?
HNPCC –> mismatch repair leading to colon cancer
Ataxia telangiectasia which is a defect in the ATM gene (recognizes DNA damage) which will lead to increased x ray sensitivity and thus breast cancer
BRCA2 which is a defect in the repair by homologous recombination which can lead to breast, ovarian and prostate cancer
Xeroderma pigmentosum which results from mutation of the nucleotide excision repair which can lead to UV sensitivity and ultimately skin cancer
what are the six characteristics of cancer cells?
infinite proliferation anchorage independent resistant to growth inhibition even with cell to cell contact resistant to apoptosis de-differentiation metastatic
what gives a mass of tumor tissue the ability to adapt and survive?
heterogenicity of the cells that gives the tissue traits that represents cancer are simply the make up of individual cells that may contribute to the tissue mass in an additive fashion
cancers are based on what three factors of the tissue?
type, physio control mech, fxn of tissue
give an example of the following and explain:
gain of function mutation
loss of function mutation
oncogenes are defined as gain of function mutations as they derive from previously inactive proto-oncogene sequences
tumor suppressor gene mutations are called loss of fxn oncogenes as their expression was what protected against cancer
What are the 6 classes for which c-onc exists?
c-onc is a proto-oncogene found in cells (v-onc in virus)
1 growth factors 2 hormone/gh receptors 3 signal transduction proteins 4 GTP-binding proteins 5 nonreceptor kinases 6 transcription factors
What activates the cell cycle? keeps it running? regulates it?
activated by GF and hormones
runs via cyclins and cyclin dependent kinases
regulated by cyclin-dependent kinase inhibitors
what are the three ways by which protooncogenes can become oncogenes?
chem/rad mutation of gene or promotor
amplification of the proto-oncogene
gene rearrangement by binding of a strong promotor or new gene causing altered expression of the proto-oncogene
explain the MAPK pathway
upon ras activation -> activate ref -> phosphorylate MEK -> phosphorylate MAPK which then can phosphorylate two things
AP-1 which activates jun/fos
transcription factors that induce myc/fos
both lead to cell proliferation
what activates the ras pathway?
growth factor binding to a g-protein receptor
define NF-1
it is a tumor suppressor which fxn to activate activate rasGTPase which inactivates ras from activating ref
defect in NF-1 will cause neurofibromatosis
explain rb-1
rb-1 is a gene that creates rb(retinoblastoma protein) which is a tumor suppressor product
rb fxn to halt cell cycling at G1 phase via binding to E2F1 transcription factors
loss or mutation of rb-1 leads to retinoblastoma in young children/infants
what is the fxn of E2F?
E2F initiates G1/S cell cycle transition period, thus rb binding will arrest cycling at the G1 checkpoint
name the 4 key regulators of the cell cycle that are commonly dysregualted in cancers
p16/INK4
cyclin D
CDK4
Rb
Explain how retinoblastoma can be de novo or inherited
rb-1 in sporadic retinoblastoma is initially normal and requires mutations of both sets of chromosome 13 at the long arm to cause cancer
rb-1 in familial retinoblastoma needs only one mutation of chromosome 13 due to a defective rb-1 in the other chromosome being passed down from the parent
what is p53 and the three things it does in response to dna damage/hypoxia?
p53 is a transcription factor
- halts DNA synthesis to prevent replication of damaged DNA
- activates DNA repair mechanisms
- initiates apoptosis if damage is too severe via BAX gene or if DNA repair fails
what can damage p53 or p27 genes lead to?
defective p53 can cause Li Fraumeni syndrome in which >25 fold incidence of cancer
p27 defect will lead to a loss of cyclin/cdk inhibition which served to block entry into S phase –> low p27 levels in breast cancer leads to poor outcomes
explain the fxn of HH, patched and smoothened interaction and it’s dysfunction
HH is hedgehog ligand that binds to patched receptor(tumor suppressor) which inhibits its suppression of smoothened (oncogene) which will activate GL-1 complex that activates proliferation
defect in patched -> smooth cannot be inhibited even w/o HH
defect in smooth -> GL-1 activation even w/ normal patched and w/o HH
Explain cadherin structure and cancers resulting from defects
cadherins anchor –> supported by catenin/actin intracellularly
cadherin CDH1 defect -> diffuse gastri cancer
what are secondary roles of catenins other than as support for cadherins?
they are TF that can activate myc and cyclin D1
APC or adenomatous polyposis coli inhibits beta catenin which can result in sporadic colon cancer
also inherited -> FAP/familial adenomatous polyposis
What are the extracellular and intracellular pathways of apoptosis?
removal of GF or binding of TNF extracellularly will activate caspase 8 and 10 which will activate caspase 3, 6 and 7
damage to mito will release cytochrome c that complexes with APAF-1 which will then activate caspase 9 which will then activate caspase 3 and 6
Describe three subsets of BCL-2 and their fxn
anti-apoptotic -> Bcl-2 binds to proapoptotic and APAF-1 to inhibit apoptosis
channel forming proapop -> Bax -> already on mito membrane and forms pores so Cyto C can be released -> inhibited by Bcl-2
BH3 proapop -> Bid/Bim/Bad -> binds to Bax to activate and binds to Bcl-2 to inactivate as well as unbind APAF-1
describe the conditions and result of the philadelphia chromosome
it is a 9:22 rearrangement where the abl gene from 9 fuses with bcr gene on 22 and makes the 22 chromosome into a phila chromosome
abl is a protooncogene for tyrosine kinase and bcr is for b cells
results in chronic myelogenous leukemia due to constant expression of bcr (CML)
What causes burkitts lymphoma?
8:14 rearrangement where c-myc is promoted by a Ig heavy promotor thus leading to high c-myc -> high amounts of WBC
what causes neuroblastoma?
N-myc which are amplified and cut out into double minutes or elongated the chromosome with a homogenous staining region (HSR) –> both cause cell survival in certain environments
what are the four methods to targeting DNA replication in Cancer?
antifolates ie. methotrexate -> inhibs thymidilate synthase -> blocks purine synth
base analogues ie. 5-FU -> inhibs T creation from U
alkylating agents ie. cyclophosphamide/cisplastin -> heavily damages DNA -> trigger apoptosis
ionizing radiation -> heavily damage DNA -> trigger apoptosis
side note for the last two if cancer p53 is inactive, the treatment will not work
what are the two methods that interfere with the mitotic apparatus
one way chokes off blood supply
two ways target oncogenic proteins
vinblastine depolymerizes microtubs
taxol polymerizes microtubs together the wrong way
Avastine inhibs VEGF which blocks angiogenesis
Herceptin is a monoclonal Ab that blocks Her2 protein found in many breast tumors
Gleevec/imatinib 1st rational drug design to bind bcr-abl tyro kinase and inactivate it
What is the protooncogene that codes for the hedgehog receptor?
SMO
