Regulation Of Apoptosis Flashcards
Is the plasma membrane intact during apoptosis?
Yes, portions bleb off and lose their symmetry
. Requires ATP
. Cytochrome C remains w/ membrane blebs
Phagocytic cell role in apoptosis
. Engulf apoptotic cells
. Bind to phosphatidylserine on membrane surface
. Release cytokines (interleukin-10 and transforming GF B) that inhibit inflammation
. No extensive damage to neighboring cells
How long does apoptosis take?
A few hours
Reasons for cell to undergo apoptosis
. Cell damaged beyond repair
. Cell innfected w/ virus
. Cells experiencing starvation
. Effects of radiation or toxins
P53 role in apoptosis
.p53 binds to p53-responsive element w/in gene promoter of the pro-apoptotic protein Bax
Apoptosis in developing tissue
. Cell division and differentiation cause excess of cells that must be removed for normal development
. In vertebrate nervous system over half of nerve cells generated undergo cell death
Sonic hedgehog pathway
. Sends anti-apoptotic signal to allow doe cell survival w/ failure to receive signal resulting in apoptosis
. When impaired cells don’t die and have potential for developing malignancy
Internal cell death program
. Occurs if there is irreparable damage to cell
. bax protein is induced and allows cytochrome C to be released from mitochondria into the cytoplasm
. Cytochrome C activates Apaf-1 adaptor protein that activates caspase 9 of the caspase proteolytic cascade
. This results in cleavage of cellular proteins and DNA in order to affect cellular suicide
. Large protein complex forms in ATP dependent manner (apoptosome)
Death receptors
. Belong to tumor necrosis factor receptor gene superfamily
. Contain homologous cytoplasmic sequence called death domain
. Molecules like FADD, TRADD, or DAXX contain death domains so they interact w/ death receptors and transmit apoptotic signals through caspase 8 or 10 activation
Fas
. Death receptor
. Initiate apoptosis when engaged by Fas ligand
TNF-R1
. Involved in death signaling
. Death inducing capability weak compared to Fas
Caspase
. Family of proteases of cysteine protease class (Cys w/in catalytic site)
. Major effectors of apoptotic death
. Synthesized as zymogen
. Classification based on function
Caspase 1
Cytokines maturation
Caspase 2, 8, 9, and 10 function
Initiator caspase
. Possess regions or domains (caspase recruitment domain in 2/9 and death effector domain in 8/10)
. Enable protease to interact w/ molecules that regulates their activity
. Cleave inactive proenzyme forms of effector caspases resulting in this activation
Caspases 3, 6, and 7 function
Effector caspases
. Executioner caspases
. Proteolytically cleave protein substrates w/ the cell causing apoptotic death
Caspases 4 and 5 function
Inflammation
Caspase 14 function
Skin development
Caspase cascade
. Sequential activation of 1 caspase after another in orderly fashion during apoptosis initiation
. Regulated by caspase inhibitors
. Initiated by apoptosome and death receptors activating initiator caspases
. Granzyme B released from Tc cells activates effector caspases
Apoptosome activates which caspase?
9
Death receptors activates which caspases?
8 and 10
Granzyme B activates which caspases?
3 and 7
Death effector domain
. Found in inactive photo-enzyme forms of certain initiator caspases and in proteins that regulate caspase activity (FADD, Fas-assoc. death domain containing protein)
. Recruits procaspases 8/10 into death-induced signaling complex DISC
. DISc requires 2nd DED in adaptor protein assoc. w/ TNF receptors
. Formation of complex allows proteolytic activation of the caspases and eventuates in apoptosis
Targets of caspases
. Include nuclear and cytoplasmic proteins
. Nuclear lamins are structural fibrous proteins that are maint arteritis
DNA during apoptosis
. DNA fragmentation factor 45/ inhibitor of caspase activated DNAase is cleaved
. Caspase activated DNAase enters nucleus and fragments DNA into ladder pattern
T/F poly ADP ribose polymerase is proteolytically cleaved by caspases
T
Bid
. Member of the Bcl-2 family
. Proteolytically cleaved by caspases
Bcl-2 family
. Family of pro survival and pro apoptotic proteins
. Pro survival: Bcl-2 and Bcl-xL
. Pro death: Bak, Bid, Bax
.
What occurs after death receptor activates caspase-8?
. Catalyze cleavage of Bid into a truncated form (tBid)
. Bak and Bax then translocate to outer mitochondrial membrane, permeabilize it, and facilitate release of pro-apoptotic proteins (cytochrome C and Smac that stop apoptosis inhibitors)
What cancers have seen an overexpression of anto-apoptotic proteins in Bcl-2 family?
. Lymphoma . Breast cancer . Prostate cancer . Lung carcinoma . Melanoma
Autoimmune conditions in relation to apoptosis
. T cells that recognizer self fail to undergo apoptosis
Neurodegenerative illness in relation to apoptosis
. Altered apoptosis in schizophrenia
. Localized apoptosis in Alzheimer’s can cause cognitive decline
. HIV-associated dementia caused by caspase 3 activating in brain
