Lecture 7: APOPTOSIS AND TUMOR SUPPRESSION Flashcards
Final Material
What is apoptosis?
Cell’s own molecules are ultimately responsible for its death
What is necrosis?
The cell is a victim of molecules synthesized by other cells; for example, necrosis results from the effects of toxic molecules on a cell.
What is Pyroptosis?
It is highly inflammatory and is in response to some intracellular pathogens or non-infectious stimuli. Pyroptosis is a caspase-1 dependent process that results in the release of the inflammatory cytokines IL-18 and IL-1β.
How does tumor-supressor gene keep cell numbers down?
Tumor-suppressor genes keep cell numbers down, either
- by inhibiting progress through the cell cycle and thereby preventing cell birth particles or
- by promoting programmed cell death (also called apoptosis).
What happens tumor-suppressor genes are rendered non-functional?
When cellular tumor suppressor genes are rendered non-functional through mutation, the cell becomes malignant. One example is the p53 gene, which inhibits cyclin-dependent kinases and is inactivated in many different tumors.
What does oncogenes stimulate?
Oncogenes stimulate appropriate cell growth under normal conditions, as required for the continued turnover and replenishment of the skin, gastrointestinal tract, and blood
What is an example of mutant oncogenes?
Ras, activated in pancreatic and colon cancers
Bcl-2, activated in lymphoid tumors. Amplification of oncogenes (more than their normal gene copy number) is also found in cancer: e.g., MDM2 is amplified in liposarcomas.
What are characteristics of BCL2/BCL-xl?
Transmembrane protein
contains Bcl-2 Homology (BH) domains BH1-4
Localizes to outer mitochondrial membrane, ER, perinuclear membrane, but not plasma membrane.
Heterodimerizes with pro-apoptotic family members such as Bax
What is the purpose of BCL-2/BCL-xL?
Functions to repress many, but not all, apoptotic pathways
serves as a pro survival function by preventing the release of mitochondrial contents such as cytochrome c that would lead to caspase activation
What happens when we have too much MDM2?
Too much MDM2 can cause cancer because it inhibits p53 which prevents cell death
What are the 2 classes of Caspases?
Initiators
Effectors (excutioners)
What are features of Caspases?
The initiation of the cascade reaction is regulated by caspase inhibitors.
All caspases have a similar domain structure
Not all mammalian caspases participate in apoptosis: For example, Caspases 4, 5, and 12 are activated during innate immune responses and are involved in the regulation of the inflammatory response
What is the role of effector caspases?
Effector caspases (such as caspase-3, -6 and -7 in mammals) function to breakdown cell structures through cleavage of specific substrates.
What Is the role of IAP Family?
they inhibit apoptosis, specifically through binding and inhibiting caspases
Describe the ways apoptosis occurs?
- Pore-forming
- Superantigen, such as enterotoxins from Staphylococcus aureus
- Toxins interfere with host signaling (AB toxins )
- Some bacterial pathogens use type-III secretion apparatus to deliver a set of effector proteins into the host cytosol
What are ways that microorganisms cause induction of apoptosis?
- activation of host cell receptors that signal for apoptosis
- induction of second messengers
- regulation of caspase activity
- inhibition of protein synthesis
- disruption of cytoplasmic membrane
what is an intrinsic defense mechanism by the host in response to microbial infection?
Cell death and infection
What are the examples of cell death mechanisms?
apoptosis, necrosis, pyroptosis
what are the two steps in necrosis?
from normal cell, it goes to:
- irregular chromatin clumping, mitochondria swells
- cellular components disintegrate, membrane rupture
what are the steps in apoptosis?
from normal cell it goes to:
- compaction and segregation of chromatin, convolution of nuclear outline
- nucleus fragments, cytoplasm condenses, cell surface protusion, membrane bound apoptopic bodies,
- phagocytosis of apoptopic bodies
- degradation by lysosomal enzymes
- digestion within lysosomes
what organism was used as a genetic model for determining apoptopic pathways?
C. elegans (the worm)
Why is the ratio of BCL-2/Bax important?
Ratio of Bcl-2:Bax important in determining susceptibility to death
What occurs in cells with oncogene mutants?
cells with gain-of-function mutant oncogenes continue to grow (or refuse to die) even when they are receiving no growth signals.
what is important about BH3?
BH3 only proteins bind and regulate the anti-apoptopic BCL-2 proteins to promote apoptosis
