Apoptosis

What are inhibited in cancer cells?

process and signals that promote apoptosis (cell death)

Why is apoptosis important?

balancing cell survival and death is crucial for maintaining homeostasis

Name some examples of apoptosis in normal tissues:

• fetal limb development

• developing nervous system

• adult liver

How does apoptosis work in fetal limb development?

tissue between fingers and toes starts out webbed → individual digits separate as cells between them die

How does apoptosis work in a developing nervous system?

matching number of nerve cells to number of target cells require innervation → unmatched nerve cells die

How does apoptosis work in the adult liver?

phenobarbital stimulates liver cell replication; stopping phenobarbital → excess cells die off + liver returns to original size

necrosis

cell death from external injury → loss of membrane integrity

• swelling/bursting into surrounding area

• typically induces inflammation

apoptosis

cell death from internal process (but is started by an external signal)

• caspase enzymes are activated

• nuclear + cytoplasmic cytoskeleton collapses → nuclear DNA is digested → membrane shed as “blebs” → endocytosed by macrophages

• limits/prevents inflammation

caspases

family of cysteine aspartic acid specific proteases

• highly specific for what proteins are degraded

• cleave protein after recognizing a 4 amino acid sequence in it

• normally present in healthy cells as inactive precursor enzymes (zymogens) w/ little to no protease activity

initiators

subgroup of caspase; auto-activates and initiates proteolytic processing of other caspases; important in controlling start of process

effectors

subgroup of caspases; activated by upstream initiator caspases; important in carrying out majority of substrate digestion during apoptosis

extrinsic pathway

receptor mediated pathway triggered by external signals from other cells

external signals (peptide) bind receptor → caspase 8 (initiator) auto-activates → activates downstream effector caspases + other enzymes → cleavage of BID → apoptosis

intrinsic pathway

mitochondrial pathway triggered by internal stress

• causes Bax and/or tBID insertion in mitochondrial membrane

• disrupted mito membrane → release of several proteins and Ca²⁺ → Ca²⁺ activates initiator caspase 9 → activation of effector enzymes → apoptosis

What causes high Bax & Bax-related levels? How is it balanced out?

high metabolic rate + number of mutations → high Bax levels

must be balanced out by high Bcl-2 levels

How do Bcl-2 inhibitors affect apoptosis of cancer cells?

Bcl-2 inhibitors occupy Bcl-2 surface → prevents interaction with Bax/Bcl-2 insertion into mito membrane → mito membrane disrupted → apoptosis

Explain the enzyme cascade POST initiator caspases:

1.) effector caspases digest ICAD (inhibitors for DNAase)

2.) CADs move to nucleus → digest DNA between nucleosomes

3.) caspases move to nucleus → digest lamins

4.) digest microfilaments

5.) digest adhesion plaque proteins

6.) digest translation factors