Transcript Apoptosis , necrosis, and death

Apoptosis, necrosis, and
death
Chapter 18
Continuity of life
• Only from existing cells come new cells.
• We are all decedents of the first cells on the
planet.
• A cell reproduces by duplicating its contents
and then dividing into two
• This cycle of events is known as the cell cycle
Consideration
• How do cells duplicate their contents?
• How do they partition the duplicated
contents and split into two?
• How do they coordinate all the
machinery that is required for these two
processes?
Cell division timing
• Different cells have cell cycles of
different lengths;
– Nerve Cells = never
– Human Liver Cells = 1 year
– Intestinal epithelial cells = 12 hours
– Yeast cells = 1.5 to 3 hours
– Bacteria = 90 minutes
Eukaryotic Cell Cycle
18_02_four_phases.jpg
Eukaryotic Cell Cycle
• Four phases
– M phase (mitotic phase)
– G1 phase (Gap 1)
– S phase (synthesis phase)
– G2 phase (Gap 2)
Central Control
• The cell-cycle control system regulates
the entire process
• A great analogy is to think of it as a
washing machine control knob
• Cannot implement the next program
until the first one in completed.
• Feedback systems operate to provide
information on how processes are
progressing.
18_03_control_system.jpg
Checkpoints
• The cell cycle halts at various points
until signals are sent to proceed
18_04_Feedback.jpg
Cycle regulation
• The key players are the kinases and
phoshatases
IMPORTANT PRINCIPLE
• Proteins may have phosphate groups added to
certain amino acids
• These phosphates are added by enzymes called
KINASES
• Proteins may have phosphate groups removed from
certain amino acids
• These phosphates are removed by enzymes called
PHOSPHATASES
• The same proteins may be repeatedly activated and
deactivated by simply adding or removing phosphate
groups
The cell-cycle is regulated by the phosphorylation of special
proteins called Cdks (shown in red). However, these proteins
must associate with other peptides before they become
functional. These other peptides are known as cyclins (shown
in green).
18_05_ Cdks.jpg
The cell just regulates the concentration of different cyclins
(hence their name - as they vary in concentration during the
cell cycle)
The cyclin which drives cells into M phase is called M-cyclin. It
interacts with a kinase called M-Cdk.
Levels of M-cyclin build steadily.
Then it is rapidly removed from the cell by rapid degradation by
the proteasome
18_06_M_Cdk.jpg
Removal of M-cyclin results in the inactivation of M-Cdk and
the cell divides.
APC (anaphase promoting complex) decides when to remove
M-cyclin from the cell.
The key molecular event that marks many proteins for
destruction by the proteasome is ubiquitation - a type of
modification.
Here the M-cyclin is ubiquitinated and is thus quickly destroyed.
18_07_cyclin_degradat.jpg
The Go (G zero) state results in the dismantling of most of the
replication machine. Nerve and muscle cells are in this state.
Many other cells come to this important checkpoint each time
after they have divided.
18_16_G1_checkpoint.jpg
In conclusion, the cell is faced with a number of points in the cell
cycle where it has to satisfy certain molecular requirements before
it is permitted to continue along the cell cycle.
18_17_arrest_checkpt.jpg
Cell Death
• The body is very good at maintaining a
constant number of cells. So there has to
exist mechanisms for ensuring other cells in
the body are removed, when appropriate.
• Two forms
– Apoptosis - suicide - programmed cell death
– Necrosis - killing - decay and destruction
Cell Death -occurs more often than one imagines!
a) Most embryo development involves programmed cell
death.
18_18_sculpts_digits.jpg
18_19_tadpole_frog.jpg
b) The tail of the tadpole is absorbed via apoptosis.
Also, in adult multicellular organisms cell death is a regular
occurrence. In humans EACH HOUR we lose many many
BILLIONS of cells via apoptosis. Most of these are healthy cells
which have no defects. WHY?
Development and regulation controls.
i.e. B and T cells are removed that do not pass certain tests.
Apoptosis results in a quick and clean cell death, without damaging its
neighbours, or eliciting an immune response. Every cell is equipped with
the ‘cell death pathway’. Apoptosis is an intracellular proteolytic
pathway. The DNA is broken into small 200 bp units.
18_20_Apoptosis_.jpg
The cytoplasm shrinks. The mitochondria release cytochrome c. The
outer surface of the plasma membrane gets coated with a different
sugar - one that macrophages can sense and phagocytose.
Caspases
• Proteins which degrade other proteins
are employed by apoptosis - caspases
• Made as inactive precursors procaspases
• These are activated by other proteins
when the right signal is received
• One caspase cleaves the lamin proteins
resulting in the irreversible breakdown
of the nuclear membrane.
18_21_proteolytic_cas.jpg
18_22_Bcl_2_family.jpg
Control of cell numbers and
cell size
• Three processes operate to control the
eventual form a body part takes
– Cell growth
– Cell division
– Cell death
• Single celled organisms grow as fast as they
are able to limited by factors such a food
availability
• Multicellular organisms receive signals from
other cells in the body
• These signals can be classified into
three catergories
– Mitogens - these allow the cell to enter the
cell cycle
– Growth factors - increase in cell mass
– Survival factors - suppress apoptosis
18_25_growth_factors.jpg
18_27_nerve_target.jpg
18_28_regulating_Bcl2.jpg