Apotosis, Cell Death, and the Proteins Associated with Them

1. Apotosis, Cell Death, and the Proteins Associated with Them

2. What is Apoptosis? • A form of programmed death • characterized by bledding of the plasma membrane, condensation of cytoplasm and nucleus, and cellular fragmentation into membrane apoptotic bodies • understanding components and functions will help in the treatment of diseases such as cancer

3. Proteins that play a role • ICE-like proteins • FAS • FAS Ligand • BCL-2 • p53

4. p53 A new set of experiments has shown that cotransfection of a plasmid encoding wild type p53 reduced the transformation potential of plasmids encoding p53 and an activated Ha-ras gene. Furthermore, wild type p53 was shown to suppress transformation by a mixture of E1A or myc and an activated Ha-ras gene. These transformation experiments indicate that wild type p53 is a suppressor of cell transformation in vitro. Curtsy of http://perso.curie.fr/Thierry.Soussi/p53_story.html

5. The expression of p53 in different human cancers or in tumor cell lines has long been under study by several different investigators. This expression is often high, but no precise explanations exist for this phenomenon because apart from the case of several osteosarcomas, no gene rearrangements, detectable by Southern blotting, have been detected. Genetic analysis of colorectal cancer reveals a very high rate of heterozygous loss of the short arm of chromosome 17, which carries the p53 gene. PCR analysis and sequencing of the remaining p53 allele shows that it often contains a point mutation. Similar observations have been made in the case of lung cancer. On the heels of these initial observations have come several hundred reports of alterations of the p53 gene in all types of human cancer. Curtsy of http://perso.curie.fr/Thierry.Soussi/p53_story.html

6. BCL-2 It is homologous to ced-9 and is involved in inhibiting ACD. Bcl-2 was first identified in Bcell lymphoma (thus, Bcl) as a result of a chromosomal translocation which lead to high expression of Bcl-2 in these tumors. The tumors subsequently developed as a result of a reduced rate of normal cell turnover; in other words, they grew due to a lower than normal rate of ACD. All members of the Bcl-2 family (except Bad and Bid) contain a hydrophobic C-terminus which serves to anchor these proteins to membranes. Bad lacks this sequence and is, therefore, located throughout the cytoplasm. Courtesy of: http://cord.ubc.ca/~steeves/~chris/bcl2.htm

7. FAS and FAS-Ligand • Fas is a cytokinase receptor and is found on cell membranes. • Fas ligand binds to Fas. • Both Fas and Fas ligand are found on activated T cells. • Fas triggers apoptosis…the death domain within Fas actually signals cell death. • Fas induces apoptosis when bound by Fas Ligand. • Image found at http://www-nmr.cabm.rutgers.edu/~gardino/page37.html

8. FAS and FAS Ligand • Fas is important for removal of autoreactive T cells…this keeps the immune system at a state of homeostasis. • Fas induced apoptosis is important in the removal of cancer cells by cytotoxic T cells and NK cells which express Fas L. • It is now believed that some tumors prevent Fas from relaying signals to the death machinery or produce Fas ligand to avoid immune-mediated apoptosis (Duke, Ojecius, and Young, “Cell Suicide in Health and Disease, Scientic American, Dec 1996, p34). • Image of apoptosis found at http://www.ed.ac.uk/~mig/apopt/migapo.html

9. ICE • Interleukin-1 converting enzyme (ICE) • ICE is activated by the apoptotic signal • the signal is caused by the binding of the FAS ligand to the FAS/Apo-1 receptor • the binding results in rapid stimulation of ICE