APOPTOSIS “Cell Death” By Brian Abadie, Emily Anderson, andJohn Ramsey

Characteristics of Apoptosis  Shrinks  Blebbing  Nucleus breaks down, breaks into small membrane wrapped fragments  Phagocyte signals  Apoptosis Video Apoptosis Video

Importance of Apoptosis  Maturing organisms  Virus  Immune System  DNA damage

What is a Caspase?  Single chain of pro-enzymes  Contains an N-terminal domain, a small subunit and a large subunit (similar to a ribosome)  Apoptotic stimulus  Activation  Substrate Cleavage  Enzyme

3 Types of Caspases  Inflammatory Caspases: -1, -4, and -5  Initiator Caspases: -2, -8, -9, and -10  Long N-terminal domain  Interact with effector caspases  Effector Caspases: -3, -6, and -7  Little to no N-terminal domain  Initiate cell death

Two Caspase Pathways Extrinsic Pathway  Death Ligand  Death Receptors  Caspases  Cell Death

Intrinsic Pathway  Mitochondria  Cytochrome C  Apoptosome Complex  Caspases  Cell Death Two Caspase Pathways

Cancer and Apoptosis   Evasion of apoptosis can lead to cancer

Treatment Options  Activate apoptosis in cancer cells, problem solved.  Finding useful mechanisms  Needs to be selective  Pathways (trail)  IAPs  Seaweed?

IAPs  Inhibitor of Apoptosis Proteins Neutralize them or prevent their production  Inhibit one part in the cascade = failure to apoptose  Smac mimetics  Bcl proteins  Elevated Bcl Confers resistance to chemotherapy

Gene Expression  Down regulation of XIAP Most potent endogenous IAP  Using Adenovirus vector  ShRNA achieves delivery And long term inhibition