Week 1 Flashcards
Five different properties of malignant cancer cells
1) Unresponsive to normal signals for proliferation control
2) De-differentiated (lack specialized structures/functions)
3) Invasive (outgrowth into normal neighbors)
4) Metastatic (shed and proliferate)
5) Clonal in origin (derived from single cell)
Cancer is the accumulation of ____________ over time. Cancer ________ can be inherited in a ______ or _______ pattern
many somatic genetic alterations and mutations
Susceptibility
Dominant or recessive
4 steps for carcinogenesis
1) Tumor initiation
2) Tumor promotion
3) Tumor conversion
4) Tumor progression
Carcinogenic mutations can occur in two types of genes, ________ and ______
Oncogenes
anti-oncogenes (Tumor Suppressors)
Oncogenes
Genes that normally stimulate cellular proliferation - are activated in carcinogenesis
= Gas Pedal
Tumor Suppressors (anti-oncogenes)
normally inhibit cellular proliferation - inactivated in carcinogenesis
= Brakes
Types of cytogenetic abnormalities associated with malignancy: (3)
1) Translocations and gene deletions
2) Loss of heterozygosity
3) aneuploidy
Events that can produce loss of heterozygosity (2)
1) Mitotic recombination
2) Loss of chromosome or translocation
The Retinoblastoma Gene is on chromosome ______ and acts as a ___________
chr13q14
tumor suppressor
Patients with “inherited” RB are ________ for the RB gene in their normal tissues and ________ for the RB gene in their tumor cells. Patients with inherited RB therefore typically have ________ retinoblastomas
heterozygous
homozygous
bilateral
Patients with no family history of RB must have ________ in order to get a retinoblastoma. Patients in this case thus typically have ______ retinoblastomas.
- two independent events occurring in retinal cells that cause both copies of RB gene to be non-functional.
- unilateral RBs
RB is hyperphosphorylated in _________ cells at ________ stage of the cell cycle
rapidly proliferating
at S or G2 of the cell cycle
__________ phosphorylates RB protein and causing it to be _________. _______ levels fluctuate while ______ levels are always the same.
CDKs + Cyc complexes
-inactivated
Cyc level fluctuates, CDK level always the same
When RB is phosphorylated in no longer is able to _______________
inhibit transition into S phase, allowing cell division cycle to begin
RB is hypophosphorylated in _________ cells at _______ stage of the cell cycle. When RB is not phosphorylated it _____________
non-proliferating cells
at G0 or G1 of the cell cycle
inhibits entry into S phase
RB is a target for many ______________. These drive a quiescent cell into S phase by producing __________
animal tumor viruses
viral proteins
_________ and ________ are examples of animal tumor viruses.
SV40 and HPV
HPV virus infects cells causing them to produce ________ and _______ proteins which inhibit _______ and ________ respectively
HPV E7 and E6 proteins
RB and p53 tumor suppressors
______, ________ and _______ are homologs that act as tumor suppressors. Their activity is _________.
RB, p107, p130
tissue specific
The APC gene is a ________ and when mutated, is involved in _________. APC gene is located on chromosome _____
Tumor suppressor gene
Familial Adenomatous Polyposis (FAP)
chr5q
Familial Adenomatous Polyposis is inherited in a _________ pattern, and requires loss of hederozygosity in adenomatous polyps of the colon to cause _____________
autosomal dominant
colon cancer by age 50
APC gene encodes a protein that regulates localization of ____________.
Beta-Catenin protein
B-Catenin protein is typically bound to _________ and kept sequestered in the _________. When B-Catenin is free in the cytoplasm, the _______ acts to break it down. Without this, B-catenin will _________
E-Cadherin, kept sequestered in plasma membrane
APC protein
enter the nucleus and activate transcription of oncogenes (c-myc)
BRCA1 and BRCA2 to function in ________.
DNA repair
Inherited BRCA1/2 cases result from __________. Acquired cases of _______ mutations in these genes have NOT been found in tumors (different from RB gene)
LOH –> mutant/non-functional BRCA1/2
Somatic mutations
If you are heterozygous for BRCA2 mutations = ___________
If you are homozygous BRCA2 mutations = ___________
This means that BRCA2 is ________ with __________
Heterozygous –> breast cancer due to LOH in mammary gland cells
Homozygous –> Fanconi’s anemia
BRCA2 is allelic with Fanconi’s anemia D1 gene FANCD1
p53 is a ________ gene that acts as ___________ by preventing ___________
tumor suppressor
“Guardian of the genome”
potentially deleterious mutation
Cellular functions of p53 (4)
1) Transcription Factor
2) Required for apoptosis
3) Mutation “hotspots”
4) Interfered with lifecycle of many human viruses
P53 acts as a transcription factor, and is important for ____________
preventing cells from replicating damaged or foreign DNA
p53 is required for apoptosis by __________
preventing cells with DNA damage beyond repair from replicating
Why was p53 originally thought to be an oncogene instead of a tumor suppressor?
“Dominant Negative” p53 mutations - heterozygous p53 mutation can produce mutant protein that binds the wild-type p53 protein and inactivates it
Oncogenes were first discovered in ________. Normal cells are ________ while cancer cells are ________
oncogenetic retroviruses (RNA viruses that infect cell and take over its replication machinery)
anchor dependent
NOT
Viral ongogne (V-onc) proteins allow viruses to _________
rapidly transform appropriate infected cells to malignant phenotype
pp60v-src is a ________ and ________ that acts to _____________
viral oncogene protein and membrane bound kinase
phosphorylate tyrosine residues of proteins causing changes in gene expression
v-erb-B is a ________ that codes for a protein similar in structure to _________, and acts as a tyorsine specific protein kinase that __________
viral oncogene protien
EGFR (epithelial growth factor cell surface receptor)
stimulates growth
v-abl is a ________ that acts as a protein kinase. v-abl is similar to ________
viral oncogene protein
human c-ABL gene (the one found in BCR-ABL translocation in CML) - Philadelphia Chromosome
Endogenous oncogenes are called _______. They are part of normal functioning human cells and must undergo _________ in order to become carcinogenic. Therapy therefore can only target _________
c-onc
mutation
c-onc over-expression (not all c-onc genes)
Oncogenes and tumor suppressor genes are being used as ________ in ________ and _______
“molecular markers”
cancer diagnosis and prognosis
“Heat Map” in personalized medicine
used to correlate many types of molecular data aka bioinformatics (gene copy number, gene expression, heat maps, mutations, etc.) with relevant clinical information (tumor grade, survival, age, tumor stage, etc.)
Breast cancer Xpress Chip
personalized medicine
info used for diagnosis, prognosis and therapy
-Measures expression of 123 genes known to be altered in breast cancers
-high erbB2 –> treat with Herceptin
High ER levels –> treat with tamoxifen
Criteria for classifying Li-Fraumeni Syndrome (3)
must have all 3
1) Proband with a sarcoma diagnosed before age 45
2) First degree relative with cancer under 45
3) A first or second-degree relative with any cancer under 45 years of age or a sarcoma at any age
Knudson Two Hit Hypothesis: Li-Fraumeni Syndrome
Hit 1 = premalignant
Hit 2 = Carcinoma
Multi-locus model - hits can be on two different genes (unlike RB)
Hit 1 LFS con occur via…(4)
1) Point mutation –> oncogene activation (RAS, myc) or tumor suppressor inactivation (p53, RB)
2) Amplifications/deletions
3) Epigenetic silencing by methylation
4) Insertion of retrovirus containing oncogenes
Hit 2 LFS
Amplification of HER2 oncogene
P53 response to UV exposure
1) p53 bound by mdm2
2) DNA damage, cell abnormalities or hypoxia –> p53 activated
3) Cell cycle arrest (DNA repair, cell cycle restart) or apoptosis/elimination of damaged cells
Von Hippel-Lindau clinical manifestions
Formation of cystic and highly vascularized tumors in many organs
- Cerebellar/Spinal cord hemangioblastomas (Major cause of death in VHL patients)
- Clear Cell Renal Cell Carcinoma (Major cause of death in VHL patients)
- Retinal Hemangioblastomas
-Must have 2 criteria: one VHL lesion + family history, or two VHL lesions
VHL inheritance is _______ with high _______ and ________
AD
penetrance and variability (severity/onset)
VHL is caused by a mutation in a ___________ gene located on __________. This gene codes a protein that is part of a complex that _____________ and ________. It is _______ dependent.
tumor suppressor
chr3p25-26
targets unwanted proteins for proteosomal degradation by ubiquination and Hypoxia Inducing Factor (HIF)
oxygen dependent
Under normal oxygen, HIF is __________. If VHL ubiquinates HIF, then ________
hydroxylated by proline and asparagine hydroxylase
proteosomal degredation
Under hypoxic conditions, HIF is ____________. HIF thus _______ and activates ________________.
not hydroxylated and not degraded
accumulates
activates transcription of genes involved in angiogenesis, metabolism, apoptosis, low O2 survival, and other cancer growth promotion processes
Cells with a mutated or lost VHL gene behave like ___________. This results in ______________
they are constantly hypoxic
HIF accumulation, aneuploidy, disruption of primary cilia maintenance → renal cysts and renal cell carcinoma formation
The VHL gene 4 actions:
1) Regulate HIF
2) Suppress anuploidy
3) Maintains primary cilia
4) Stabilizes microtubules
Clear Cell Renal Cell Carcinoma (ccRCC) follows the ________ theory because two copies of _________ are required
Two-hit
inactive VHL gene
The lipid bilayer is a ______ and _______ structure. The lipid molecules are constantly _______ - catalyzed by ________
dynamic and fluid
changing places with its neighbors in the bilayer
Flippase (ATP driven)
Membrane fluidity depends on ______ and ______. _______ decreases fluidity.
Composition and temperature
cholesterol
Phospholipid is a _______ molecule synthesized in the ________. It does not __________.
amphipathic
ER
spontaneously flip/flop
Most common Phospholipids include _________, ________, and ___________, and are all derived from __________
Phosphatidylethanolamine (PE)
Phosphatidylserine (PS)
Phosphatidylinositol (PI)
glycerol
Sphingolipid is a _______ molecule synthesized in the ________. _______ is an example, derived from ____________
amphipathic
ER
Sphingomyelin
Sphingosine
Cholesterol is a _______ molecule synthesized in the _______. It is made up of a ________, _________ and ________.
Amphipathic
ER
Polar hydroxyl group
Hydrocarbon tail
Rigid steroid ring (intercalates with hydrophobic tails)
Cholesterol is important in ________ and ______, therefore its abundance is carefully regulated.
Determining membrane fluidity and membrane thickness
less cholesterol = more fluid and thinner
The cell membrane is ________, which is established during __________.
Assymetrical, established in ER during synthesis
Negatively charged molecules (PS, PE, PI) are more abundant on _________, while PC, sphingomyelin, and glycolipids are more abundant on _______. _________ is equally distributed.
internal surface
external surface
Cholesterol
HMGCoA Reductase is the _________ in cholesterol synthesis and is a target for __________
first/rate limiting step
Statins (treat high cholesterol)
Sterol Regulatory Element Binding Protein (SREBP)
Transmembrane protein
- Binds transcription factor keeping it inactive
- when cholesterol is low –> TF cleaved from SREBP in golgi by proteases
