Cell Cycle (Cell Death) Flashcards
The development and maintenance of multicellular organisms depend not only on cell growth and cell division but also on ____ _____
Cell Death
cells die at the same rate as they are produced
maintenance of tissue size
programmed cell death; “falling off”
Apoptosis
rapidly engulfs the cell and fragments before they can spill their contents.
Macrophages
-cells that die in response to an acute insult.
-swell and burst, spilling their contents eliciting inflammatory response
cell necrosis
a form of programmed cell death that is triggered by a specific regulatory signal from other cells
necroptosis
cell death help sculpt hands and feet during _________ ___________.
embryonic development
also functions as a quality-control process in development, eliminating cells that are abnormal, misplaced, nonfunctional, or potentially dangerous to the animal.
Apoptosis
must be tightly regulated to ensure that they are exactly in balance
cell death and cell division
cell can kill themselves by undergoing apoptosis
damages (DNA damages)
triggered by members of a family of
specialized intracellular proteases
Apoptosis
have a cysteine at their active site and cleave their target proteins at specific aspartic acids
caspases
begin the apoptotic process; apoptotic signal -> assembly of large protein complexes -> dimers -> protease activation
initiator caspases
initiator caspases activate ___________ ________
executioner caspases
inactive dimers; cleaved by an initiator caspase at a site in the protease domain -> rearranged to active form ->amplifying proteolytic cascade-> kill the cell
executioner caspases
-cleavage -> irreversible breakdown of nuclear lamina
-a protein that normally holds a DNA-degrading endonuclease (iCAD) in an inactive form; its cleavage frees the endonuclease (CAD) to cut up the DNA in the cell nucleus
lamins
self-amplifying and irreversible
caspase cascade
How is the initiator caspase first activated in response to an apoptotic signal?
-extrinsic pathway and intrinsic and intrinsic
-mitochondrial pathway
Is signaled from outside the cell
intrinsic pathway
Is signaled from mitochondria inside the cell
mitochondrial pathway
transmembrane proteins; extracellular ligand-binding domain, a single transmembrane domain, and an intracellular death domain
death receptors
The receptors are homotrimers and belong to the _____ ________ ______ ________ family.
tumor necrosis factor (TNF) receptor
TNF has eight members, which includes?
-a receptor for TNF itself
-Fas death receptor
ligands are also ___________
homotrimers
activation of Fas
binding of Fas ligand -> death domains on the cytosolic tails bind intracellular adaptor proteins -> bind initiator caspases -> death-inducing signaling complex (DISC) -> activate executioner caspapses
help prevent the inappropriate activation of the extrinsic pathway of apoptosis.
inhibitory proteins-FLIP
depends on the release into the cytosol of mitochondrial proteins
intrinsic or mitochondrial pathway
released proteins activate a caspase proteolytic cascade in the cytoplasm, leading to _________
apoptosis
released into the cytosol -> binds to an adaptor protein called _____ (apoptotic protease activating factor-1) -> oligomerize into a wheel-like heptamer called ______ -> recruit initiator _____-_ proteins
cytochrome c
- Apaf1
- apoptosome
- caspase-9
major class of intracellular regulators of the intrinsic pathway
Bcl2 family
suppress apoptosis; controlling the release of cytochrome c and other intermembrane mitochondrial proteins into the cytosol
Bcl2 family
classes of mammalian Bcl2 family proteins
- Anti-apoptotic Bcl2 family proteins
- Pro-apoptotic Bcl2 family effectors
anti-apoptotic
bcl2 and BclXL
Pro-apoptotic
effector Bcl2 family proteins and Bh3-only proteins
activation of intrinsic pathway
apoptotic stimulus
Bcl2 family aggregate to form oligomers in the mitochondrial outer membrane
activation of intrinsic pathway
apoptotic stimulus → activated _____ pathway →
____ family aggregate to form oligomers in the
mitochondrial outer membrane → release of
____ _
intrinsic
Bcl2
cytochrome c
main effector of intrinsic pathway
Bax (cytosol) and Bak (mitochondrial outer membrane)
cytosolic surface of the outer mitochondrial membrane; help prevent inappropriate release of intermembrane proteins
Anti-apoptotic: Bcl and BclXL
-to promote apoptosis mainly by inhibiting anti-apoptotic Bcl2 family proteins
-enables the aggregation of Bax and Bak on the surface of mitochondria, which triggers the release of the intermembrane mitochondrial proteins that induce apoptosis.
BH3-only proteins
DNA damage -> tumor suppressor protein __ accumulates and activates the transcription of genes that encode the BH3-only proteins ____ and _____ ->trigger the ___ pathway
p53
Puma and Noxa
intrinsic
cell employs multiple ______ __________ to ensure that these proteases are activated only when appropriate
robust mechanisms
-Another lone of defense against inappropriate caspase activation is provided by caspase inhibitor proteins called
-first identified in certain insect viruses (baculoviruses), which encode IAP proteins to prevent a host cell that is infected by the virus from killing itself by apoptosis.
inhibitors of apoptosis (IAPs)
destruction for proteosomes
polyuquitylate caspases
IAP-binding domain which binds to the BIR domain of IAPs, preventing the domain from binding to a caspase
anti-IAPS (Drosophila)-Reaper, Grim, and Hid
are released from the mitochondrial intermembrane space when the intrinsic pathway of apoptosis is activated, blocking IAPs in the cytosol and thereby promoting apoptosis.
Anti-IAPs
inhibit apoptosis
extracellular survival factors
nerve cells are produced in excess in the __________ _______ ______
developing nervous system
receive enough signal survival signals live, while others die.
compete for limited amounts of survival factors
the number of surviving _______ is automatically adjusted so that it is appropriate for the number of target cells they connect with
neurons
bind to cell-surface receptors, which activate intracellular signaling pathways that suppress the apoptotic program, usually by regulating the expression or activity of members of the Bcl2 family of proteins.
survival factors
thereby enabling IAP proteins to suppress apoptosis
phosphorylating and inactivating anti-IAP proteins such as Hid
the apoptotic cell and its fragments do not break open and release their contents, but instead remain intact as they are efficiently eaten or ____________ by neighboring cells.
phagocytysed
chemical changes on the surface of the apoptotic cell recruit __________ _____
phagocytic cells
located exclusively in the inner leaflet of the lipid bilayer, but it flips to the outer leaflet in apoptotic cells
phosphatidylserine
healthy cells express signal proteins on their surface that interact with inhibitory receptors on macrophages that block phagocytosis
macrophages do not phagocytose healthy cells
cells die by necrosis as a result of ischemia
heart attacks or strokes
inactivate the genes that encode the Fas death receptor or the Fas ligand
conditions where too few cells die by apoptosis
accumulate in spleen and lymph -> autoimmune disease
prevent normal death of some lymphocytes
tumors, cancer cells regulate their apoptotic program abnormally
decreased apoptosis
-chromosome translocation causes excessive production of the Bcl2 protein; B cell lymphoma
-development of cancer by inhibiting apoptosis; decrease the cells’ sensitivity to anticancer drugs
Bcl2 gene
-gene encoding the _____ __________ ______ ___ is mutated in about 50% of human cancers
-can no longer promotes apoptosis or cell-cycle arrest in response to DNA damage
-enables the cancer cells to survive and proliferate even when their DNA is damaged
tumor suppressor protein p53
small chemical that interfere with the function of anti-apoptotic Bcl2 family proteins
drugs that stimulate apoptosis
spade-like structures →individual digits
separate only as the cells between them die
cells die when the structure they form is no
longer needed →
tadpole to frog; tail is not
needed in the frog
two major classes of
apoptotic caspases
initiator caspases and executioner caspases.
initiator caspases - begin the apoptotic
process;apoptotic signal →
triggers the assembly of large protein
begin the apoptotic
process; apoptotic signal → assembly of
large protein complexes →
caspases associate to form dimers
begin the apoptotic
process; apoptotic signal → assembly of
large protein complexes → dimers →
protease activation
executioner caspases - inactive dimers;
cleaved by an initiator caspase at a site
in the protease domain →
rearranged to
active form
Inactive dimers;
cleaved by an initiator caspase at a site
in the protease domain → rearranged to
active form →
amplifying proteolytic
cascade
inactive dimers;
cleaved by an initiator caspase at a site
in the protease domain → rearranged to
active form → amplifying proteolytic
cascade →
kill the cell
a protein that normally holds a ___-______ ______ in an
inactive form; its cleavage frees the
________ to cut up the DNA in
the cell nucleus
DNA-
degrading endonuclease (iCAD)
endonuclease (CAD)
proteins that are cleaved by caspases during apoptosis
- nuclear lamins
- a protein that normally holds a DNA-
degrading endonuclease (iCAD) in an
inactive form - components of the cytoskeleton and cell–
cell adhesion proteins
inhibit apoptosis mainly by
binding to and inhibiting
pro-apoptotic Bcl2 family
proteins
anti-apoptotic
