Test 4. Lecture 37 Flashcards
Introduction (general)
Cell death and proliferation are balanced throughout the life of
multicellular organisms.
Animal development involves cell proliferation and differentiation and also
cell death.
- Most cell death occurs by a normal process of programmed cell death.
Most tissues have stem cells that can replace cells that have been lost. - Abnormalities of cell death are involved in cancers, autoimmune
diseases, and neuro-degenerative disorders.
But the ability of stem cells to proliferate and differentiate makes them a
promising mechanism for replacing damaged tissues
- Programmed cell death is carefully regulated.
In adults, it BALANCES CELL PROLIFERATION AND MAINTAINS CONSTANT CELL NUMBERS
It also eliminates DAMAGED AND POTENTIALLY DANGEROUS cells (e.g., virusinfected
cells).
During development, programmed cell death plays a key role by
_______________ from many tissues.
Examples: Elimination of larval tissues during amphibian and insect
metamorphosis. E
eliminating unwanted cells
Necrosis: Accidental cell death from ______________
acute injury
_____________: Programmed cell death; an active process. Characterized by:
- DNA fragmentation
- Chromatin condensation
- Fragmentation of the nucleus and cell
Apoptosis
Apoptotic cells and cell fragments are
recognized and phagocytosed by
macrophages and neighboring cells, and rapidly removed from tissues.
Necrotic cells swell and lyse; the contents are released into the extracellular space and cause
inflammation.
Apoptotic cells express “____________” signals, such as
______________.
In normal cells, phosphatidylserine is
restricted to the inner leaflet of the
plasma membrane
eat me
phosphatidylserine
The genes ___________and _______ are required for developmental cell death.
A third gene, __________, is a negative regulator.
These genes are the central regulators and effectors of apoptosis that are highly
conserved in evolution.
ced-3 and ced-4
ced-9
Ced-3 is the prototype of the _______________- family of proteases.
Caspases have cysteine (C) residues at their active sites and cleave after aspartic acid
(Asp) residues in their substrate proteins.
Caspases are the ____________ of programmed cell death by cleaving over
100 different target proteins.
Activation of an initiator caspase starts a chain reaction of caspase activation leading
to death of the cell.
caspases
ultimate executioners
___________ is closely related to the ____________, which was first identified as an oncogene. Bcl-2 inhibits apoptosis. Cancer cells are unable to
undergo apoptosis.
Mammals encode about 20 proteins related to Bcl-2, in three functional groups. Some inhibit apoptosis; others induce caspase activation.
The fate of the cell is determined by the balance of activity of ____________and Bcl-2 family members
ced-9 in C. elegans
mammalian gene bcl-2
proapoptotic and
antiapoptotic
__________ are the
downstream effectors that
directly induce apoptosis.
They are inhibited by
antiapoptotic Bcl-2.
BH3-only members are upstream; when activated by cell death signals, they antagonize the Bcl-2 family and activate Bax and Bak.
Bax and Bak
In mammal cells, Bcl-2 proteins act at the mitochondria, which play a
central role in controlling programmed cell death.
____________induce release of cytochrome c which triggers caspase
activation.
Caspase-9 is the key initiator caspase. It is activated by forming a
complex with Apaf-1 and cytochrome c in a complex called the ___________
Under normal conditions,
1. cytochrome c is located in the mitochondrial inter-membrane space;
2. Apaf-1 and caspase-9 are in the cytosol, so caspase-9 remains
inactive
Bax and Bak
apoptosome.
Regulation of programmed cell death is
mediated by signaling pathways; some
induce cell death and others promote
cell survival.
Intrinsic pathways are activated by DNA
damage and other cell stress.
Extrinsic pathways are activated by signals from other cells. A major pathway leading to cell cycle arrest in response to DNA damage is mediated by\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
ATM and Chk2 protein kinases
phosphorylate and stabilize p53,
resulting in rapid increases in p53
levels.
p53 then activates transcription of genes
encoding the proapoptotic BH3-only
proteins PUMA and Noxa, leading to cell
death.
the transcription factor p53.
A major signaling pathway that promotes cell survival is initiated by the enzyme-________, which phosphorylates PIP2 to form PIP3, which
activates the protein-serine/threonine kinase __________
Akt phosphorylates a number of proteins that regulate apoptosis
PI 3-kinase
Akt.
Extrinsic pathway
Polypeptides in the_____________
_______ family are the signals.
Receptors activate an initiator caspase,
caspase-8.
Caspase-8 can cleave and activate
effector caspases and Bid, which
leads to activation of caspase-9.
tumor necrosis factor (TNF)
- Programmed cell death can also occur by non-apoptotic mechanisms
such as _____________.
In normal cells, autophagy is a mechanism for gradual turnover of cell
components.
In starvation conditions, degradation of components provides energy and
recycles materials.
- Autophagic cell death does not require____________.
Dying cells are characterized by an accumulation of lysosomes. It can be activated by cellular stress and provide an alternative to apoptosis
when apoptosis is blocked.
autophagy
caspases
Most differentiated cells in adult animals are no longer capable of
proliferation.
If these cells are lost they are replaced by proliferation of cells derived
from self-renewing stem cells.
Some differentiated cells retain the ability to proliferate as needed, to
repair damaged tissue throughout the life of the organism.
Fibroblasts in connective tissue can proliferate quickly in response to
_______________ released at the site of a wound.
platelet-derived growth factor (PDGF)
