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49 Cards in this Set

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In response to DNA lesions, what is the role of FOXO1 in response to blocked CDK2 activity?
What is the role of BRCA2?
FOXO1 -> prodeath gene expression.
BRCA2 -> DNA repair.
There is a counteraction / balance between FOXO1 and BRCA2.
Science 13 oct 2006 vol 314 no 5797 pp261-262
Name the role of ubiquitination in the pathogenesis of:
- anthrax
- Yersiniosis
- many viruses, which encode for E3 Ub ligases
- Anthrax toxin triggers ubiquitination of its receptor -> endocytosis -> low pH endosomal compartment -> toxicity of toxin.
- Yersinia produces YopJ -> YoPJ acts as a deubiquitination enzyme -> NF-kappaB activation is prevented.
- E3 Ub ligase (named modulator of immune recognition 1 of KSHV) -> ubiquitination, endocytosis and degradation of MHC class I molecules.
Science 12 Jan 2007 vol 315 no.5809 pp.201-205
How does increase in cytosolic calcium lead to pores in the mitochondrial membranes?
cytosolic Ca up -> mitochondrial Ca up (because mito membrane potential is maintained) -> mitochondrial permeability transition -> pores (=< 1.5 kDa).
Ann.Rev.Path. vol.1 pp405-434 2006
Function of survivin?
- member of inhibitor of apoptosis (IAP) gene family; inhibits apoptosis by binding of caspase-9 or blocking of SMAC.
- binds to microtubules of mitotic spindle to maintain a normal bipolar mitotic apparatus.
- expressed during embryonal development, absent in terminally differentiated normal tissues.
- upregulated in several human cancers.
Vet Pathol 41:599-607 (2004)
What is the role of phosphatidylserine on cells dying by apoptosis?
- PS (normally limited to the inner leaflet of the cell membrane) stimulates macrophage PS receptor (PSR) -> phagocytosis.
- Suppressive pathways that prevent phagocytes from mounting a proinflammatory response. TGFbeta-1 plays a role in this suppression of inflammation.
Science 28 nov 2003 vol 302 p.1516
Questions on autophagy:
1. what is TOR kinase?
2. how can autophagy promote cell survival?
3. how can autophagy be activated?
4. how can autophagy be inhibited?
5. how can autophagy prevent cancer?
6. how can autophagy promote cancer?
1. an enzyme that senses nutrient status, regulator of cell growth, negative regulator of autophagy-execution proteins.
2. nutrient recycling and housekeeping function.
3. by many signals that activate apoptosis: sphingolipids, death-receptor signalling molecules, serine/threonine death kinases, mitochondrial-associated death proteins.
4. regulators of apoptosis of Bcl-2 family can disarm autophagy-execution proteins such as Beclin 1.
5. 1) death-promoting, 2) prevent DNA damage by housekeeping: removing sources of oxidative stress; 3) negatively regulates growth.
6. through survival of normal cells during nutrient starvation.
Nature 445,745-747, 12 april 2007
Name 5 caspase substrates.
- nuclear proteins
- transcription factors and cell-cycle regulators
- caspase-sensitive kinases
- cytoskeletal proteins
- proinflammatory cytokines
AJP sep 2006 vol 169 no 3 p.729 (table 2)
Explain how apoptosis-inducing factor (AIF) is involved in a form of cell death which follows the morphological pattern of apoptosis but does not involve caspase activation.
AIF, a free-radical scavenger oxidoreductase, is normally confined to mitochondria. After mitochondrial injury, AIF translocates into the nucleus to initiate DNase activity.
AJP sep 2006 vol169 no3 p.729
How can apoptosis be a result of early phase sepsis?
Early phase sepsis: bacteria and their byproducts stimulate macrophages to release pro-apoptotic substances such as TNFalpha, NO, glucocorticoids.
(during sepsis: massive apoptotic loss of lymphocytes; caspase-9/mitochondrial pathway)
EID 2007 feb 13(2):191-8.
What is the recently proposed 'trinity' of pathogen receptors cooperating in innate immunity?
Which cytokine is important particulary in respons to viral RNA detection?
- NOD-like receptors (bacteria)
- Toll-like receptors (viruses, bacteria, fungi, protozoa)
- RIG-like receptors (viruses)

In response to viral RNA detection: type I interferon production.
Science 314 10 nov 2006 p.935
In sepsis, give an example of:
1. excessive cellular activation
2. depressed cellular function
3. too little apoptosis
4. too much apoptosis
1. neutrophils: excess toxic products -> damage
2. neutrophil failure to phagocytize and clear invading pathogens
3. neutrophils -> damage
4. lymphocytes -> poor immunity
AJP vol 170 no 5, may 2007
In sepsis-induced coagulation in the baboon lung, does the level of TFPI go up or down?
And TF?
TFPI down.
TF up.

May explain the coagulation.
AJP vol171 no3 sep 2007
Name biological functions of these acute phase proteins:
1. C-reactive protein
2. Serum amyoid-A
3. Haptoglobin
4. Alpha-1-acid glycoprotein
5. Ceruloplasmin
1. when bound to bacteria, promotes phagocytosis; induction of cytokines; inhibition of chemotaxis and modulation of neutrophil function.
2. chemotaxis; downregulation of inflammation.
3. antagonist for receptor-ligand activation of immune system; bactericidal.
4. antiinflammatory and immunomodulatory.
5. transport of Cu for wound healing, collagen formation and maturation; protects against oxidants; reduction of neutrophil attachment to endothelium.
Vet Clin Path vol 34 no 2 2005 p.87
1. activation leads to the formation of which products?
2. name 3 activators of NF-kB
3. name an inhibitor of NF-kB
1. iNOS, COX-2, IL-8, eotaxin, ICAM-1, VCAM-1, and IkB-alpha (autoreg.).
2. TNFalpha, protein kinase C (PKC), oxidants (H2O2).
3. glucocorticoids
LI 2006 86 867-872
Regarding the role of p53 in cardiac hypertrophy:
Draw a figure showing the relationships between cardiac hypertrophy, ischemia, HIF-1, p53, VEGF, angiogenesis and heart failure. Use arrows to indicate positive and negative influences among these factors.
See figure.
Nature vol 446 22 march 2007
Genome mutations
loss or gain of whole chromosomes
-> monosomy or trisomy
Robbins p.147
chromosome mutations
rearrangement of genetic material

-> visible structural changes in the chromosome
Robbins p.147
gene mutations
submicroscopic. may result in deletion of a whole gene or a single base
Robbins p. 147/148
missense mutation
mutation leading to altered meaning of the genetic code (different amino acid)
Robbins p. 147/148
conservative missense mutation
missense mutation with little change in the function of the protein
Robbins p. 147/148
nonconservative missense mutation
missense mutation in which the amino acid is replaced with a very different one
Robbins p. 147/148
nonsense mutation
mutation leading to a stop codon
Robbins p. 147/148
How can mutations within noncoding sequences cause deleterious effects?
They can be in regulatory sequences and interfere with binding of transcription factors.
Robbins ch5
both alleles of a gene pair fully expressed in the heterozygote
Robbins ch5
pleiotropism of a gene mutation
many end effects
Robbins ch5
genetic heterogeneity
mutations at several loci produce the same trait
Robbins ch5
DNA polymorphism
a DNA change that occurs in at least 1% of the population (not causing disease)
Robbins ch5
Reduced penetrance of a gene mutation
some individuals inherit the mutant gene but are phenotypically normal
Robbins ch5
variable expressivity
a trait is seen in all individuals carrying the mutant gene but is expressed differently among individuals
Robbins ch5
Two major categories of nonenzyme proteins affected in autosomal dominant disorders
1. those involved in regulation of complex metabolic pathways that are subject to feedback inhibition (LDL receptor)
2. key structural proteins (collagen, cytoskeletal elements of erythrocyte membrane)
Robbins ch5
dominant negative mutant allele
mutant allele impairs the function of a normal allele
Robbins ch5
inborn errors of metabolism: usual mode of inheritance?
autosomal recessive
Robbins ch5
male with mutant gene on the X chromosome
Robbins ch5
1. accumulation of the substrate
2. metabolic block and a decreased amount of end product that may be necessary for normal function
3. failure to inactivate a tissue-damaging substrate
Figure 5-7 Scheme of a possible metabolic pathway in which a substrate is converted to an end product by a series of enzyme reactions. M1, M2, products of a minor pathway.
The biochemical consequences of an enzyme defect in such a reaction?
Robbins ch5
Name important defects in lysosomal storage diseases, other than lack of lysosomal enzyme.
Synthesis of a catalytically inactive protein that cross-reacts immunologically with the normal enzyme. Thus, by immunoassays the enzyme levels appear to be normal.
Defects in post-translational processing of the enzyme protein. Included in this category is a failure to attach the mannose-6-phosphate "marker," the absence of which prevents the enzyme from following its correct path to the lysosome. Instead the enzyme is secreted outside the cell.
Lack of an enzyme activator or protector protein.
Lack of a substrate activator protein. In some instances, proteins that react with the substrate to facilitate its hydrolysis may be missing or defective.
Lack of a transport protein required for egress of the digested material from the lysosomes.
Robbins ch5
Describe the synthesis and intracellular transport of lysosomal enzymes.
See figure.
R fig 5-11
One quarter of canine lymphomas show which aberration of chromosome 13?
McG p283
A missense mutation has been identified in the Birt-Hogg-Dubé (DBH) gene in German shepherd dogs with which diseases?
- hereditary multifocal renal cystadenocarcinoma
- nodular dermatofibrosis
McG p284
Which genetic alteration is found in the c-kit gene in canine mast cell tumors?
Internal tandem duplication.
McG p.284
What is characteristic of DNA methylation in cancer?
- overal decrease in 5-methylcytosine in the bulk of the genome (global hypomethylation)
- paradoxal increase in gene-specific methylation of clusters of CpG sites in the promoter and/or exon 1 of genes (CpG islands).
McG p.284
In general, does hypermethylation of genes (particular promoter regions) lead to gene activation or silencing?
(exception: paradoxical promoter methylation in cancer)
McG p.284
Draw the pathogenetic mechanism by which (human) papillomavirus causes neoplasia.
See figure (from Robbins)
How does histone acetylation affect transcription?
DNA is wound around histones. The presence of acetyl groups (Ac) on histone tails is associated with relaxed chromatin, which is permissive to gene transcription. Removal of acetyl groups by histone deacetylases results in a closed chromatin configuration that is less permissive to the transcription machinery.
McG p285 fig 6-40
How are mature miRNAs made from primary transcripts (pri-miRNAs)?
Name 2 regulatory small noncoding RNAs. name functions and differences between the two.
Processed by two RNase III enzymes: Drosha and Dicer.

regulatory small ncRNAs: siRNAs and miRNAs. both have a similar mechanism for gene expression regulation.
siRNAs: often exogenous. from long dsRNAs or long hairpins.
miRNAs: endogenous. from short hairpin precursors. more important. usually target sequences at other loci.

miRNAs are aberrantly expressed in diverse cancers, thought to be both tumor suppressors and oncogenes. This article: aberrant miRNA in hypertrophic heart.
mRNA targets of miRNA are complex, with perfect / imperfect complementarity, and one miRNA may have multiple mRNA targets.
AJP 170:6 june 2007
What can be measured in gene expression profiles?
What is array-based comparative genomic hybridization?
What is tissue microarray?
mRNA levels across thousands of genes simultaneously.
Array CGH: tumor and normal genomic DNA labeled and compared by hybridization to microarrays comprising DNA probes of defined genome map position. Tumor/normal ratios mapped to reveal amplifications and deletions which drive altered expression of cancer genes.
TMA: cylindrical tissue cores from several hundred different tumor specimens sectioned on one glass slide to measure a single gene's expression across many samples.->also info on cellular location of expression.
AJP 171:2 August 2007
Role of transforming growth factor beta in cancer?
In inflammation?
In wound healing?
Cancer: TGFbeta suppresses progression of early lesions, but later, cancer cells produce TGFbeta-> metastasis, angiogenesis, immunosuppression.
Promotes wound healing.

Contributes to apoptosis control, angiogenesis, wound healing, immune regulation and tumor biology.
LI 2007 1-15
miRNAs: how are they made?
2 possible roles microRNAs in tumorigenesis?
primary miRNAs (pri-miRNAs) transcribed from miRNA genes by RNA polymerase II, spliced, polyadenylated.
Processed by the RNAase enzyme Drosha to pre-miRNAs.
Transport from nucleus to cytoplasm by Exportin-5, and processed by Dicer (another RNAase III enzyme) -> miRNA:miRNA* hybrids.
Binding to Argonaut-> miRNA* released -> RISC (RNA interference silencing complex).
Deregulation-> transcription miRNA due to altered gene copy number, methylation of promoter, or changes in activity of TFs.
1. accumulation miRNA that normally regulates tumor suppressor-> underexpression of tumor suppressor.
2. underexpression of miRNA that controls proto-oncogene -> excess product.
And they can themselves be transcriptional targets of oncogenes and tumor suppressor genes.
AJP 2007 171:728-738
Name 4 proteasome-independent functions of ubiquitin.
What are similarities between protein ubiquitination and phosphorylation?
Regulation of:
- cell division
- differentiation
- signal transduction
- protein trafficking, and quality control.
Both ubiquitination and phosphorylation: proteins are specifically, diversely, and reversibly modified.
Science 12 Jan 2007 vol 315 no.5809 pp.201-205
Name functions, outside of the death pathway, where caspases have been implicated.
- keratinocyte differentiation
- lens cell differentiation
- erythrocyte differentiation
- platelet formation
- cell fusion
- monocyte differentiation into macrophages and dendritic cells
- clonal expansion of T and B lymphocytes.
AJP sep 2006 vol 169 no 3 p.729