19.3 Programmed Cell Death Flashcards
() balances cell proliferation and potentially dangerous cells (e.g. virus-infected cells, cells with damaged DNA/mutated DNA)
programmed cell death
3 main events in apoptosis:
- DNA fragmentation
- chromatin condensation
- fragmentation of nucleus
membrane-enclosed fragments that result from the apoptosis of cells
apoptotic bodies
how are cells that die by apoptosis rapidly removed from tissues
apoptotic bodies are efficiently recognized and phagocytosed by both macrophages and neighboring cells
apoptopic cells express () on their surface
‘eat me’ signals (e.g. phosphatidylserine)
apoptosis causes () to be expressed on the cell surface, where it is recognized by receptors expressed by phagocytic cells
phosphatidylserine
studies of () by Horvits and colleagues identified 3 genes with key roles in apoptosis:
C. elegans
studies of C. elegans by Horvits and colleagues identified 3 genes with key roles in apoptosis:
- Ced-3
- Ced-4
- Ced-9
(1) and (2) are genes that are required for developmental cell death
Ced-3 and Ced-4
Ced-9 serves as a () in apoptosis
negative regulator
Ced-3 was found to be the prototype of the ()
caspases (a family of proteases)
() was found to be the prototype of the caspases (a family of proteases)
Ced-3
called caspases due to the presence of (1) at their active sites and they cleave (2) in their substrate proteins
- cysteine (C) residues
- aspartic acid (Asp) residues
the () are the ultimate effectors/executioners of programmed cell death; they bring about apoptosis by cleaving more than 100 different target proteins
caspases
activation of an () starts a chain reaction of caspase activation leading to cell death
initiator caspase
main targets of caspases in apoptosis
- DNase inhibitor
- nuclear lamins
- cytoskeletal proteins
- Golgi matrix proteins
- scramblase
caspases targeting DNase inhibitor results in DNase activation, which in turn results in ()
nuclear DNA fragementation
caspases cleave nuclear lamins to result in ()
fragmentation of nucleus
caspases cleave cytoskeletal proteins to result in ()
cytoskeletal disruption, cell fragmentation, and PM blebbing (irregular bulging)
caspases cleave Golgi matrix proteins to result in ()
fragmentation of Golgi
caspases also cleave and activate a () that translocates phosphatidylserine to the outer leaflet of the PM
scramblase
higher eukaryotes have families of at least 7 caspases that are classified as either (1) or (2) caspases
- initiator
- effector
all caspases are synthesized as inactive precursors called ()
procaspases
procaspases are converted to the active form by () (catalyzed by other caspases)
proteolytic cleavage
() caspases are activated in response to various signals
initiator
() are cleaved and activated by initiator caspases and then act to digest cellular target proteins
effector caspases
Ced-9 was found to be closely related to a mammalian gene called (), an oncogene that contributed to the development of B-cell lymphomas
bcl-2
instead of stimulating cell proliferation, bcl-2 was found to ()
inhibit apoptosis
2 major classifications of Bcl-2 family members
- antiapoptotic regulatory proteins
- proapoptotic proteins
proapoptotic proteins can be further divided into
- proapoptotic regulatory proteins
- proapoptotic effector proteins
act to induce caspase activation and promote cell death
proapoptotic proteins
inhibit proapoptotic effector proteins (e.g. Bcl-2) and are regulated by signals that induce cell death or survival
proapoptotic regulatory proteins
downstream effectors that directly induce apoptosis
proapoptotic effector proteins
activated proapoptotic regulatory proteins initiate apoptosis by 2 mechanisms:
- antagonize antiapoptotic regulatory proteins
- activate proapoptotic effector proteins
in mammals, Bcl-2 family proteins act at the ()
mitochondria
proapoptotic effector proteins (1) oligomerize to form pores in the outer mitochondrial membrane to release (2)
- Bax and Bak
- cytochrome c
release of () triggers caspase activation
cytochrome c
key initiator caspase in mammalian cells
caspase-9
caspase-9 is activated by forming a complex with (1) in a multisubunit complex called (2)
- Apaf-1
- apoptosome
pathways that regulate programmed cell death are either:
- intrinsic pathways
- extrinsic pathways
programmed cell death regulatory pathways that are triggered by DNA damage and other cell stress
intrinsic pathways
intrinsic pathways are triggered by (1) and other (2)
- DNA damage
- cell stresses
the multiple signals that activate intrinsic apoptosis regulatory pathways converge on regulation of ()
proapoptotic regulatory Bcl-2 proteins
programmed cell death regulatory pathways that are triggered by signals from other cells
extrinsic pathways
extrinsic apoptosis regulatory pathways are activated by ()
signals from other cells
give examples of intrinsic pathways that regulate apoptosis
- p53 pathway
- Akt/PI 3-kinase pathway
transcription factor p53 mediates a major pathway that leads to cell cycle arrest in response to ()
DNA damage
the Akt/PI 3-kinase pathway is an intrinsic pathway that regulates apoptosis; it responds to ()
growth factor deprivation
(1) and (2) protein kinases (activated by DNA damage) phosphorylate and stabilize p53
- ATM
- Chk2
induction of apoptosis due to increased p53 is due in part to the transcriptional activation of genes encoding () (proapoptotic regularory proteins)
PUMA and Noxa
increased PUMA and Noxa lead to activation of ()
Bax and Bak
most cells in higher animals are programmed to undergo apoptosis unless cell death is ()
actively supressed by survival signals from other cells (e.g. growth factors)
a major pathway that promotes cell survival is initiated by (1) and results in the activation of (2)
- PI 3-kinase
- Akt
how does Akt regulate proteins involved in apoptosis
Akt phosphorylates BH-3 proteins including Bad and FOXO transcription factors to inactivate them
in absence of Akt, (1) promotes apoptosis and (2) stimulates transcription of another proapoptotic BH3-only protein called (3)
- Bad
- FOXO
- Bim
example of extrinsic pathway that regulates programmed cell death
TNF-receptor signaling
polypeptides in the () family bind to receptors and activate an initiator caspase
tumor necrosis factor
polypeptides in the tumor necrosis factor family bind to receptors and activate an initiator caspase called ()
caspase-8
caspase-8 cleaves and activates (1) and (2), which leads to the activation of (3)
- effector caspases
- Bid
- caspase-9
() - provides a mechanism for the gradual turnover of the cell’s components through lysosomes
autophagy
autophagy can lead to cell death by ()
degradation of essential cell components
accidental cell death from acute injury; causes swelling and bursting of the cell
necrosis
unlike apoptosis, autophagy does not require ()
caspases
in necrosis, cell contents are released into extracellular space and cause ()
inflammation
regulated necrotic cell death
necroptosis
