Week 6 Review - No Path Flashcards
Do activated cyclin-dependent kinases promote cell cycle progression, or do they stop the cell cycle?
They promote cell cycle progression
Name three ways the cell controls the activity of CDKs.
- Phosphorylation - ACTIVE when phosphorylated.
- Degradation via Ub-proteasome.
- Transcriptional changes.
What is a CKI?
CDK inhibiting protein
Describe the normal function of an activated (phosphorylated) CDK-cyclin.
CDK-cyclin-P phosphorylates (inactivates) Rb –> keeps Rb from holding onto E2F –> E2F goes to nucleus to upregulate DNA synthesis enzyme transcription
What is p53? How does the p53 protein work?
It is a tumor suppressor that can sense DNA damage in both G1 and G2 cell cycle stages. If DNA damage is present, p53 stops the cycle and upregulates p21 transcription. p21 is a cyclin-dependent kinase inhibitor (CKI) that helps stop the cell cycle to allow for DNA repair.
Name one disease that is characterized by inheritance of one defective p53 gene, predisposing patients to multiple cancers all over the body.
Li-Fraumeni syndrome
A 8-week old baby presents to your clinic with an absent red reflex in one eye. What do you suspect and what is the mechanism behind this?
Hereditary retinoblastoma - inheritance of one defective Rb gene. Rb protein is unable to sequester E2F –> constitutive transcription of DNA synthesis genes –> high susceptibility to developing eye tumors and other cancers.
Do receptor tyrosine kinase pathways promote growth, or apoptosis?
Growth
Which protein is ultimately phosphorylated in the PI3K receptor tyrosine kinase pathway that promotes cell survival?
RTK ligand binding –> bunch of steps –> activated PKB (aka Akt) dissociates from membrane to phosphorylate Bad –> inhibition of apoptosis
What is the function of the Ras protein in the Ras/MAPK RTK pathway?
It is activated by SOS guanine exchange factor (grab help, Ras!), Ras-GTP activates his brother Raf (a MAPKKK) –> –> MAPK –> promotion of cell growth and division
What would happen if the GAP (GTPase activating protein) on Ras became mutated? Is there an example of this that we learned?
Constitutive cell growth promotion by MAPK –> cancer
Yeah! Neurofibromatosis type 1 (NF1) is exactly this!
How many mutations of a proto-oncogene are required for loss of growth inhibition?
one
How many mutations of a tumor suppressor gene are required for loss of growth inhibition?
two
A defect in the ____________ pathway is thought to be the underlying mechanism for Lynch syndome-associated cancers. The molecular hallmark for this disease is _________ instability.
DNA mismatch repair and microsatellite instability
What is APC and what does it do? What cancer syndrome is it associated with?
APC is a tumor suppressor that binds beta-catenin, keeping beta-catenin from going to the nucleus to upregulate transcription of growth-promoting genes.
Hereditary APC mutation is associated with familial adenomatous polyposis syndrome (FAP)
What causes Fanconi Anemia? Name 4 clinical manifestations.
Mutation in FANC (DNA repair gene)
- Short stature
- Developmental delay
- Odd wrist curvature
- Missing or extra digits
What cellular process are the BRCA gene products involved in?
DNA repair
What are the hallmarks of familial cancer syndrome?
- Early age of onset
- Multiple primary tumors
- Positive family Hx for cancers
What do topoisomerases do?
Relieve positive supercoiling during DNA replication.
What is the most common DNA single nucleotide substitution?
C –> T
Telomerase adds nucleotides to the ___ (5’ or 3’) end of a DNA strand by using its hTR subunit to serve as a template for elongation, while the ______ subunit adds 6 nucleotides at a time. After that, ________ ________ fills in nucleotides on the complimentary strand.
telomerase adds nucleotides to the 3’ end using the TERT subunit and DNA polymerase fills in the lagging strand using the newly-elongated section on the parental, leading strand
Which DNA repair mechanism is used to repair spontaneous deamination?
base excision repair
What type of DNA lesions do UV light cause? Which repair mechanism fixes this? Did we learn of a disease associated with a defect in this repair pathway?
UV light –> pyrimidine dimers.
Fixed by nucleotide excision repair.
Xeroderma pigmentosum = defect in both GG and TC-nucleotide excision repair pathways.
Cockayne syndrome = defect in the XPB/XPD helicases in the TC-NER pathway. Causes neurodegeneration but not cancer.
Which repair pathway is involved in correcting single base pair errors resulting from DNA replication?
mismatch repair
Name three diseases that are associated with trinucleotide repeat expansion.
- Fragile X
- Myotonic dystrophy
- Huntington’s disease
With trinucleotide repeat disorders, what effect does repeat number have on the clinical phenotype?
More repeats –> earlier onset and increased severity of the disease
What causes ataxia telangiectasia?
mutation of ATM, which is involved in double-stranded break repair
What is the function of MGMT? What role does it play in cancer cell regulation?
It is a repair methyltransferase that gets rid of methyl (and ethyl) groups from cytosines on DNA. If cancer cells express MGMT, they are able to get rid of the methyl groups that cancer drugs put on cancer cell DNA –> cancer cell survival
In order to fight a cancer, would you want to methylate the MGMT gene?
Yeah! That would turn off transcription of the MGMT gene –> no ability to remove methyl groups from DNA in cancer cells
What are the seven hallmarks of cancer?
See you at II am
- Self sufficiency in growth signals
- Evading apoptosis
- Evading immune system
- Insensitive to growth inhibition
- Immortal
- Angiogenesis
- Metastasis
Is Bcl2 pro-apoptotic, or anti-apoptotic?
Anti-apoptotic
What is RET? Which heritable cancer syndrome is associated with it?
It is a proto-oncogene (only example of heritable cancer syndrome caused by a proto-oncogene). Inherited mutation of RET = multiple endocrine neoplasia type 2 (MEN2) predisposes people to parathyroid cancer, phaeochromocytoma, and thyroid cancer
Which method of gene discovery involves looking at a family’s pedigree to identify the source of a disease-associated allele?
Linkage analysis
An association analysis is ________-based, discovery-driven, and looks for associations between genes and a particular disease.
population-based
Which HPV types are associated with cervical cancer? By what mechanism do they promote cell growth?
16, 18. HPV viral DNA gene product E6 blocks p53, E7 sequesters Rb, allowing E2F to enter the nucleus and upregulate transcription of DNA synthesis enzymes.
Describe the apoptotic pathway.
p53 senses DNA damage, stops cell cycle, induces Puma –> Puma binds Bcl-2 –> Bcl-2 dissociates from Bax –> Bad sequesters Bcl-2 while Bax oligomerizes and forms a channel in the mitochonrdial membrane –> cytochrome C leakage –> caspase activation
What is T-antigen?
A large protein made by SV40 virus that affects humans. It can block p53 and Rb to promote cell division and, hence, viral replication.
The bcr-abl fusion is associated with _____ (which disease?); it involves a translocation between chromosomes ____ and ____.
associated with CML
translocation between chromosomes 9 and 22 (Philadelphia chromosome)
In Burkitt lymphoma, there is a translocation between chromosomes ____ and ____, which puts the gene for ______ directly behind the promoter for _____, causing its overexpression.
translocation between chromosomes 8 and 14
puts the gene for c-Myc behind the promoter for IgH –> overexpression
What do both imatinib and Herceptin target?
receptor tyrosine kinases
What is the protein called that recognizes DNA mismatches?
hMutS
What is the genetic basis for multiple endocrine neoplasia type 1 (MEN1)? What types of cancer does this predispose people to?
mutation in menin, a tumor suppressor.
predisposes to pituitary, parathyroid, and pancreatic islet cell cancer
