1. Cell Death-Apoptosis Lecture 39B BSCI 420,421,620Dec 4, 2002 “It’s not that I’m afraid to die, I just don’t want to be there when it happens” - Woody Allen 1.Cell and Tissue Renewal in Animals 2.Cell death - Apoptosis

2. Cell biologists have come to realize that most cell death is not accidental (Necrosis- cell death due to injury) but is programmed cell death. Cells are killed by a regulated series of biochemical events, whereby one cell commits suicide for the good of the organism. This kind of cell death is called Apoptosis. (B & C below) (Gr. Loss of parts like leaves from a tree)

3. What do I mean by dying for the good of the whole organism? This is how our fingers emerge from a club-like paw (mouse paw Stained with a dye that labels cells in apotosis; B one day later)

4. Specific genes for Apoptosis were discovered in the nematode C. elegans. These cell death genes, when mutant, have the phenotype of failure of certain specific cells (131) to die when they should during development. Similar genes later discovered in vertebrates: RegulatorAdapterEffector Worm Ced 9Ced 4->Ced 3 ->Death Vert. Bcl-2Apaf-1->Casp 9 ->Casp3->Death Caspases are cysteine aspartases, proteases that split proteins at aspartate residues to break down cell structures

6. Fas is a cell-death receptor activated by Fas ligand on another cell such as a killer T-cell. Eg to kill a virus infected or tumor cell.

8. When DNA is damaged, eg by radiation, cells use p53 pathways to either halt cells in cycle, or to signal cell death. How is that choice made? When damage is repairable, med amounts of p53 are activated.

9. When damage is irreparable, p53 is activated at high levels and activates the transcription of several cell death genes, including: Bax – stimulates release of cyt C from mitochondria Fas – cell death receptor Apaf-1 – Apoptotic protease activating factor

10. These activate the mitochondrial cell death pathway: (Model) Bax & Bid interact w VDAC (mit porin) to cause formation of a large channel that releases cytochrome C & procaspase 9 from the intermembrane space of mitochondria. Cyt C binds to Apaf-1 activating it so it can bind procaspase 9 & form a scaffold. On this scaffold, procaspase 9 mols split each other to initiate the caspase cascade and cell death. Caspase 9 Procaspase 9 Cell Death Apaf-1 cyt C VDAC Bax & Bid

11. Suppression of Apoptosis by survival (trophic) factors

12. Bcl-2 inhibits Bax from forming cyt C release channel; Thus Bcl-2 is a major anti-apotosis factor.