Download Programmed Cell Death

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project

Document related concepts

Oncogenomics wikipedia , lookup

Gene therapy of the human retina wikipedia , lookup

Vectors in gene therapy wikipedia , lookup

Polycomb Group Proteins and Cancer wikipedia , lookup

Mir-92 microRNA precursor family wikipedia , lookup

Epigenetics of neurodegenerative diseases wikipedia , lookup

NEDD9 wikipedia , lookup

Transcript
Programmed Cell Death
Why do some cells need to die?
• To accomplish morphogenetic ends, eg. Separation of fingers
during embryogenesis of the hand
• To eliminate one potential pathway of bipotential tissues and
organs, eg. Elimination of Mullerian system through Mullerian
Inhibiting Factor in male sexual differentiation
• To accomplish metamorphosis, eg. Loss of larval structures in
insect metamorphosis
• To eliminate self-recognizing B-cell clones in development of
vertebrate immune system
• To eliminate senescent cells in organs that continuously renew
themselves, eg. The intestinal epithelium and other ectodermal
structures.
• To eliminate cells that have begun to behave abnormally, eg.
Effect of tumor necrosis factor on tumors
There are at least 3 distinct forms of
programmed cell death
• Apoptosis or type 1 cell death
– Major effect is through nuclear damage and
chromosome fragmentation – but mitochondrial
damage is also typical
– This is the best understood form
• Autophagic cell death or type 2 cell death
– Major effect is through formation of autolysosomes –
the cell digests itself
• Type 3 cell death
– Empty spaces appear in the cytoplasm
How is programmed cell death
initiated?
• Possibility #1: cells self-initiate a suicide
program unless they receive deathsuppressing growth factors.
• Possibility #2: an extrinsic signal initiates
the death program in cells that would
otherwise survive.
Nerve growth factor – an example of a
system that follows possibility #1
• Viktor Hamburger and Rita Levi-Montalcini observed that
growth and survival of embryonic motor neurons is
dependent on the presence and size of their target
tissues. Specifically, removing a limb bud from a chick
embryo results in a reduction in the number of spinal
motor neurons and sensory neurons in the
corresponding spinal segments, whereas transplantation
of an extra limb bud increased the number of neurons.
• The mediator of this is secretion of trophic factors by
the targets – including nerve growth factor or NGF. NGF
improves neuron survival and stimulates growth of
processes that will ultimately become axons. It is a
member of the family of neurotropins.
C. elegans – one of the simplest animals with a nervous system
Nervous system development in the nematode
Caenorhabditis elegans: an example of Possibility #2
• During neurogenesis, exactly 1030 neurons are
born – and exactly 131 of them die.
• Timing and location of neuronal apoptosis is
predictable in each case.
• Two genes – CED-3 and CED-4 – are required
for apoptosis – site-directed mutations that
inactivate either one prevent all developmentally
related neuron death.
• The product of CED-3 is a protease that is
activated by the product of CED-4 during
apoptosis.
How is CED-3 turned on?
• A 3rd gene CED-9 produces a product that
blocks the effect of CED-4. Mutation of CED-9
results in death of cells that would otherwise
survive, so the animals carrying this mutation
have short lives.
• CED-9 is controlled by expression of EGL-1 –
the EGL-1 gene product binds to the CED-9
gene product, inactivating it.
• These findings triggered a search for homologs
of the CED genes in mammals, and led to the
discovery of caspases.
Caspases and apoptosis
• Apaf-1 is the mammalian homolog of
CED-4 – so this is a proapoptotic gene.
• Caspases are the homologs of CED-3
• Bcl-2 proteins are the homologs of CED-9
The caspase cascade
• In healthy cells, caspases are expressed
as procaspases - zymogens, proteins that
have to be cleaved into specific pieces to
become active enzymes.
• There are two classes of caspases,
initiators and effectors (or executioners)
– Initiators, once activated, cleave executioners
– Executioners attack a wide variety of
cytoplasmic and nuclear proteins
How is the caspase cascade turned on?
• The extrinsic pathway is turned on, for example, by
ligand binding to a cell surface receptor – several death
receptors have been characterized extensively. For
example, one receptor for NGF kills the neurons that
have it, rather than stimulating them.
• The intrinsic pathway is turned on by mitochondrial
release of proapoptoptic factors, such as cytochrome c.
• Proteins in the Bcl-2 family (there are about 20 of them
in the human genome) reside in the mitochondrial inner
membrane and can prevent this release, or promote it,
depending on which particular subdomains they
possess.
Obviously, the caspase
cascade involves a number
of players. To make some
generalizations about it:
1. Caspases 3, 6 and 7 form a
common pathway that
leads to cleavage of DNA
and nuclear damage
2. Several cell-surface
receptors can address
caspaces 3, 6 and 7,
including tumor necrosis
factor TNF, the Fas ligand
FasL and growth factor
receptor binding protein
GRB.
3. A separate pathway leads
from mitochondrial damage
that releases Cyt C, to
activation of caspases 3,6,
and 7.
Apoptosis and disease
• Failure of apoptosis: autoimmune diseases like
lupus erythematosis; some forms of cancer (so
genes that regulate apoptosis are
protooncogenes – mutation of them can cause
cancer.
• Premature or excessive apoptosis:
neurodegenerative diseases such as
Parkinson’s D. or amyotrophic lateral sclerosis;
excitotoxicity in the nervous system.
Amyotrophic lateral sclerosis
• Results from apoptosis of spinal motor neurons
• Associated with a mutation in superoxide
dismutase 1, a cytoplasmic enzyme that
scavenges oxygen free radicals, so “oxidative
stress” can initiate apoptosis. If the mutant
human gene is transferred to mice, they get a
disease similar to the human one.
• Overexpression of an antiapoptotic Bcl-2 or
administration of caspase inhibitors can slow
progression of the disease in the animal model.
Molecular Pharmacology
• A majority of cancer chemotherapy drugs
act on some aspect of apoptosis.
• Trials of antisense RNAs directed against
antiapoptotic pathways are in progress.