Apoptosis Flashcards
ATM
is a serine/threonine protein kinase that is recruited and activated by DNA double strand breaks.
APAF
Apoptotic protease activating factor: complexes with cytochrome c to activate caspase 9
caspase
Cysteinyl Aspartate Proteases. Endopeptidases that cleave after an aspartate residue.
Is BH123 pro-apoptotic or anti-apoptotic?
pro-apoptotic
Is BH3 pro-apoptotic or anti-apoptotic?
pro-apoptotic
Is BH1234 pro-apoptotic or anti-apoptotic?
anti-apoptotic
What are the main BH123 proteins?
Bax, Bak
Apoptosis is induced by the release of ________ from the intermembrane space of the mitochondria. This occurs when Bac and Bak ________ on the cytosolic region of the outer mitochondrial membrane. Their aggregation here forms channels; thus allowing ________ into the cytosol; which eventually induces the caspase cascade.
cytochrome c
oligomerise
cytochrome c
In a healthy cell, ________ proteins are bound to BH1234 proteins. BH1234 proteins (e.g. Bcl-2, Bcl-Xl) are ___-apoptotic proteins; when complexed with ________ proteins, they inhibit the aggregation of Bax and Bak, hence inhibiting apoptosis.
BH123
pro
BH123
When a cell is signalled to undergo apoptosis, pro-apoptotic _____ expression is increased in the cell. _____ proteins (e.g. Bid, Bim and PUMA) inhibit the anti-apoptotic ________ proteins. BH3 proteins bind to the BH1234 proteins, rendering the BH1234 proteins unable to bind with BH123 proteins. This means the ________ proteins (Bax/Bak) are able to oligomerise and form the channels in the outer mitochondrial membrane which results in the leakage of ________ into the cytosol.
BH3
BH3
BH123
cytochrome c
Apoptosis has 3 broad steps:
initation
execution
phagocytosis
The most frequent signals that activate INTRINSIC INITIATION are ________ and ________ DNA legions. These legions lead to the activation of _____; a protein that is able to activate the tumour suppressor, ____. ____ promotes the upregulation of pro-apoptotic BH3 proteins, which bind to anti-apoptotic _____ proteins preventing the formation of ________ complexes. This means that the ________ proteins (Bax/Bak) are able to aggregate in the outer mitochondrial membrane.
irreparable irreversible ATM p53 p53 BH123 BH123-BH1234 BH123
Channels in the outer mitochondrial membrane allow ________ to escape from the mitochondrial intermembrane space into the ________. ________ then binds to ________, an apoptotic protease activating factor, which then associates with procaspase _.
cytochrome c
cytosol
Cytochrome c
APAF
As a result APAF associating with Procaspase 9, the inhibiting domain of procaspase 9 is ________, and ________ from the protease. By this mechanism, caspase 9 becomes active. Caspase 9 is able to ________ additional caspases, and destroys many other proteins. The concentration of ________ in the cell increases exponentially, leading to the destruction of many different proteins.
hydrolysed
disassociates
cleave
active proteases
A common extracellular factor that initiates EXTRINSIC INITIATION is ________ (e.g. ___/FasL), which is secreted by many cells e.g. ______ cells. TNF binds to the TNF receptor at the outer cellular membrane. Subsequently, this so called ________ (DD) at the cytoplasmic side of the receptor is activated. As a result, ________ proteins with their own DDs bind and are activated.
Tumour Necrosis Factor TNFα T-Killer death domain cytosolic
In EXTRINSIC INITIATION, the first protein that binds to the cytosolic part of the receptor is the _____________________________ (TRADD). Next, the _____________________________ (FADD) binds, and recruits Procaspase __. This protease is able to autocatalyse the ________ of its inhibiting domain, leading to caspase __ activation, which disassociates from the receptor and is then able to initiate the ________. ________ cleavage of caspase __ stabilises the active ________ in the cytosol to go on to activate ________ caspases such as caspase 3.
TNF Receptor Associated protein with Death Domain Fas Associated Death Domain hydrolysis 8 caspase cascade Autocatalytic 8 dimer executioner
EXECUTION: In a normal cell, _______ is complexed to an inhibitor and is inactive. After initiation and activation of the caspase cascade, the active caspase __ is able to cleave this inhibitor. Activated ________ cleaves DNA. Cleavage sites are located at regular intervals of ____ base pairs. In between, histone proteins of nucleosomes protect the DNA against ________ cleavage.
DNase
3
DNase
DNase
EXECUTION: Caspase 3 cleaves many proteins, such as proteins of the cytoskeleton; hereby, the cell loses its structure. Next, other proteins cause the cell to collapse into vesicles, so-called ________. Most blebs contain ________ and ________, including DNA. These components allow ________ to be maintained, and new proteins synthesised. The rapid breakup of the cell and of the formed vesicles is thus avoided, preventing an ________ reaction in the surrounding tissue.
apoptotic blebs mitochondria portions of the nucleus energy inflammatory
The various processes of the execution phase lead to significant modifications of the structure and composition of the outer membranes of cells and apoptotic blebs. Caspase __ cleaves protein XKR8 which promotes presentation of ________ on the outer leaflet of the plasma membrane. This releases a “find me” signal to surrounding phagocytes by activating ________ (PLA2) which acts on membranous ________ to release ________ which targets phagocytes, such as macrophages, in the surrounding tissue. In the cytosol of the phagocytosing cell, the blebs fuse with enzyme-filled lysosomes. These organelles finally metabolise the blebs and their components.
3 phophatidylserine phospholipase A2 phophatidylcholine lysophosphatidylcholine
