Uark Cancer Biology Exam 3
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Chapter 9: Apoptosis
A form of programmed cell death in multicellular organisms.
Is apoptosis single-step or multi-step?
Multi-step
Is apoptosis reversible once begun?
No, it is irreversible
Does apoptosis occur in single-celled organisms?
No, only multicellular organisms
What is p53?
A transcription factor functioning as a tumor suppressor in multicellular organisms.
What is the function of p53 and the nickname?
Critical in conserving stability and preventing cancer formation; called the ‘guardian of the genome’
Why is p53 a special tumor suppressor?
It doesn’t inhibit cell division like most others; will instead destroy cells
What is the result of mutated p53?
Like a house without a security system, the individual will develop cancer and die quickly, proving the importance of p53.
What is one of the most mutated genes resulting in cancer formation?
p53
Which location in the reading from is most affected by point mutations in p53?
The DNA binding domain contains 95% of point mutations in p53.
What causes a rapid increase in p53 levels?
A variety of negative environmental conditions such as lack of nucleotides, UV radiation, ionizing radiation, oncogene signaling, hypoxia, blockage of transcription, etc.
What do heightened levels of p53 do for the cell?
Controls checkpoints in cell cycle, determining senescence or continuation of proliferation.
What does X-ray exposure do to p53 levels?
Strongly increases
What does elevated p53 levels induce?
The expression of p21
What does p21 do
Acts as a potent CDK inhibitor of the cyclin-CDK complexes, halts cell proliferation in G1, S, and G2 phases.
How is p21 expression affected by mutated p53 cells?
p21 expression is absent.
What is mdm2?
A target gene for p53, expression induced by elevated levels of p53
What does mdm2 do?
Binds to p53, exports it to cytoplasm, and triggers its degradation (negative feedback loop)
What two changes can p53 induce?
Block cell cycle progression through inducing expression of CDK-I inhibitor.
If damage is too severe, p53 induces protein that triggers apoptosis.
What two proteins control p53 levels?
mdm2
ARF (p14ARF)
What is the function of ARF?
It binds and inactivates mdm2 inside the nucleus, functioning as a tumor suppressor through preventing p53 degradation.
What two things can prevent the degradation of p53?
Phosphorylation of p53 in the N-terminal domain, blocking mdm2 binding
ARF binding and inactivating mdm2.
What kinases are involved with the phosphorylation of p53?
ATM/ATR and Chk1/Chk2
What are p53 levels like in normal cells?
Very low
Which molecules are tumor suppressors and which are oncogenes?
Tumor suppressors = p53 and ARF
Oncogenes = mdm2
What does phosphorylation at the N-terminus do to p53 levels?
Increases them since p53 is not being degraded.
Where is p53 localized?
Outside of the nucleolus (this is where ribosomes are produced)
what are the 3 major features of apoptotic cells?
membrane is disrupted by blebs, making cell deformed
chromatin is very condensed and nucleus becomes smaller
DNA is fragmented when assessed under electrophoresis and gel will show fragments way further down the gel than in normal cells.
What are the two major signaling pathways that trigger apoptosis?
Mitochondrion-mediated pathway (intrinsic, stress-activated)
Receptor-activated pathway (extrinsic)
What 3 groups can the Bcl-2 protein family be divided into?
Bcl-2 family (pro-survival) 4 domains preserved
Bax family (pro-apoptosis) 3 domains preserved
BH3-only family (pro-apoptosis) 1 domain preserved
Which domain is responsible for making the cell anti-apoptosis?
BH4 domain (only present in Bcl-2 family)
Where is Bax’s location in normal cells and abnormal cells?
Normal cells = in cytosol
Abnormal cells = under stress, will move to mitochondria, forming channel on outer membrane.
What is a result of Bax drilling a hole in the outer membrane of the mitochondria?
Cytochrome C and Smac/DIABLO released and cell goes into apoptosis
What does Bcl-2 do in comparison to Bax?
Exact opposite of Bax, neutralizing Bax to keep it from drilling hole in mitochondria.
What does BH3 do in comparison to Bax?
Helps Bax. Functions as a sensor in cytosol, monitoring stresses. When DNA is damaged, it migrates to Bcl-2 and neutralizes it so Bax can continue drilling into mitochondria.
What determines the outcome of the cell’s actions with these three protein families?
The relative amount (aka the ratio) of both anti and pro-apoptotic proteins present will determine the outcome, with the higher amounted group winning.
Does the ratio or the absolute number determine the cell’s outcome?
Ratio
What is an apoptosome?
Complex formed by Apaf-1 that binds to mitochondria to activate a proteinase and converts caspase 9 into active form.
In normal cells, caspase 9 is in the _____ form.
inactive
What happens following the activation of caspase 9?
A caspase cascade, including the activation of caspase 3, 6, and 7; an irreversible process.
What are IAPs?
Inhibitors of apoptosis, keeping cells from continuing into programmed cell death after the production of caspase 3, 6, and 7.
What is the function of Smac/DIABLO?
Inhibit/neutralize IAPs (so they are pro-apoptotic proteins)
Does the production of caspases 3, 6, and 7 alone guarantee that the cell will die?
No, that is determined by IAPs.
How many cellular proteins undergo cleavage during apoptosis?
400-1000
What are 3 Major proteins dictating the 3 Major features in apoptotic cells?
Lamin
Inhibitor of DNase (ICAD)
Cytoskeletal proteins (actin, pectin, vimentin, etc.)
Where is Lamin located and what is it involved in?
On inner surface of the nuclear membrane; involved in chromatin condensation and nucleus shrinkage
What does ICAD do?
liberates DNase, responsible for fragmentation of chromosomal DNA.
What do cytoskeletal proteins do?
Lead to the collapse of the cytoskeleton; responsible for formation of blebs protruding from plasma membrane and formation of apoptotic bodies.
How many death receptors occur in the human genome?
~30
What causes receptor trimerization in receptor-mediated cell apoptosis?
Three-subunit ligand complexes binding to monomeric receptors, increasing their affinity for each other.
How do these trimerized receptors trigger apoptosis?
Tails of receptors act via FADD protein to assemble a DISC activates procaspases 8 and 10, which activate procaspases 3, 6, and 7 (caspase cascade).
How many receptors can bind w FADD at a time?
1
What are the 3 major ways that p53 activates apoptosis?
p53 induces expression of Fas receptor, attracting Fas ligand.
p53 induces expression of IGF-binding protein-3, attracting IGF-1 and IGF-2 which are pro-survival ligands.
p53 induces expression of Bax (pro-apoptotic).
What are the 2 general activities that must occur for cancer formation to occur?
Pro-apoptosis suppression
Anti-apoptosis overexpression (unlimited cell proliferation)
Chapter 10: Cell Immortalization
The ability to proliferate indefinitely
How many times to normal cells divide?
limited; 50-60 times.
What type of cells are excluded from this limited division?
Stem cells
What causes a life-threatening tumor to form?
Cancer cells must become immortalized.
What are senescent cells?
Viable differentiated cells that lose the ability to divide (appears like a fried egg under a microscope)
What is a cell lineage?
A pedigree of cells related through mitotic divison.
How many times do tumor cells need to double to generate life-threatening tumors?
40 times
Can cancer cells divide forever as is implied?
No
What leads to the loss of many cells in each generation of a pedigree?
Destroyed through apoptosis (attrition)
Can cancer cells grow exponentially?
No
What is the cell generational clock?
Measures the cumulative physiological stress and the allowed quota for a cell.
What two major components does the cell generational clock measure?
Cumulative physiological stress, and once damage exceeds a certain threshold, cells enter senescence.
Allowed quota, and once quota is used up, cells enter crisis leading to apoptosis.
What happens to cells with more exposure to oxygen?
Damage accumulates faster and they experience a quicker onset of senescence.
What do high levels of p16 and p21 result in?
Cell enters senescence.
What prevents cells from entering senescence?
The inactivation of p53 and pRb.
What was the clear result of the experiment including different mediums with p53 and p16?
p53 and p16 require a special medium to continue the growth of their cultures, preventing the early onset of senescence.
What is required to circumvent senescence?
Inactivation of BOTH p53 (affects survival) and pRb (affects division).
What is a synonym for senescence being circumvented?
Immortalization
What is the function of telomeres?
They prevent the end-to-end fusion of chromosomal DNA molecules
What does telomere length denote?
The number of cell generations (quota), as well as whether or not the cell goes into a state of crisis (super short length).
What key protein maintains normal telomeric structure?
TRF2
How quickly do typical telomeres shorten?
50-100 base pairs per cell generation.
What do the telomeric strands consist of?
tandem repeats of TTAGGG (5-10Kb)
What is an important feature to note about the G-rich strand of a telomere?
It extends beyond the C-rich strand, creating a 3’ overhang.
What is telomerase?
An enzyme that adds specific DNA sequence repeats (TTAGGG) to the 3’ end of DNA strands in the telomere regions.W
When is telomerase present in the human body?
Early in embryogenesis and is largely lost during differentiation.
When is telomerase activity detectable?
Never in normal human somatic cells, but 95% clearly detectable in human tumor cells.Wh
What subunits make up a human telomerase?
hTERT and hTR
Which strand does telomerase bind to and synthesize?
G-rich strand only
Levels of ______ expression determine the levels of the enzyme telomerase activity in the cell.
hTERTL
Levels of _____ are similar between mortal and immortal cells, so it doesn’t determine the levels of enzyme activity in the cell.
hTR
The expression of ______ prevents crisis in the cell.
hTERT
Ectopic expression of ______ enables cells to gain the ability to proliferate indefinitey. (Responsible for immortalization)
hTERT
______% of cells express telomerase activity.
85-90%
The remainder of cells (10-15%) maintain their telomere length via _______.
Alternative lengthening of telomeres (ALT)
What are the 2 main methods of ALT?
Extension using another chromosomal template.
Unequal crossing over
What is important to note about ALT?
The mechanisms of ALT are independent of telomerase.
Chapter 11: Tumorigenesis:
Production of a new tumor/tumors
Which sex and age range is cancer the most common in?
Older/elderly males
What is the correlation between cigarette consumption and lung cancer?
Highly correlated, but there are some non-tobacco related lung cancer deaths.
Does cumulative exposure to a carcinogenic stimulus or the age at which the exposure began determine the likelihood of developing a detectable tumor?
Cumulative exposure (over time)
What is the cause for carcinoma progression?
Gene mutation accumulation of the following:
loss of APC
DNA hypomethylation
activation of K-ras
loss of 18q TSG
loss of p53What
What is clonal succession?
A mutant cell spawns a large flock of descendants and that among these numerous descendants, a new mutational event will trigger yet another wave of clonal expansion.
What is another important additional piece of evidence that tumorigenesis is multi-step?
Normal cells are resistant to transformation by a single mutated gene and often require collaborations of two or more mutant genes to transform.
What were the findings in the rat embryo fibroblasts (REFs) experiment with myc, E1A, and ras?
In order for the cells to transform, the assay had to include either myc and ras or E1A and ras, never just ras or myc/E1A alone.