1. Apoptosis in Cancer By: Karen Hutcherson Ryan Jenkins Angie Lam Jennie Zaborsky ISAT 351 4-11-00

2. Apoptosis §Programmed cell death §If cells fail to destroy themselves, this could result in cancer and does not help the immune system to function. §The following proteins take part in the regulation of apoptosis: Fas, Fas ligand, ICE-like, BCL-2, and p53 tumor suppressor

3. FAS and FAS Ligand §Fas Ligand (FasL, CD95L) is a 40 kDa type II transmembrane protein of the TNF receptor (TNFR) family. §The crystal structure of lymphotoxin complex with TNFR1 suggests by analogy that each FasL trimer binds three Fas molecules. Engagement of Fas by FasL on target cells triggers a cascade of subcellular events that ends in apoptosis. §http://www.oncresprod.com/products/spotlight.asp

4. FAS/FASL System §Plays an essential role in elimi-nation of autoreactive lymphocytes and the deletion of activated T cells §Mediates the killing of virus-infected cells and cancer cells by cytotoxic T cells and by natural killer cells §Expressed in cells of the lymphoid/myeloid series and in non-lymphoid cells where it contributes to immune privilege by inducing apoptosis in infiltrating proinflammatory immunocytes §http://www.oncresprod.com/products/spotlight.asp

5. ICE-Like Proteins §Caspases or cysteine proteases are part of the ICE- like protease family which are activated during apoptosis. §Control signal transduction and the execution phase §They are protein-cleaving enzymes that kill the cell by destroying essential components that are needed to survive. §Mediate neuronal cell death under pathological conditions §Bcl-2 regulates ICE by homologous onco-proteins. l http://cbweb.med.harvard.edu/research/yuan/projects.html

6. BCL-2 §What is it? §What does it do? §How does it cause cancer?

7. BCL-2 is an proto- oncogene….. §It resides on chromosome 18 in your DNA §The gene was discovered while researching B-cell Leukemia §The region containing BCL-2 on this chromosome translocates with a portion of chromosome 14 in cancerous cells, which contains the antibody heavy chain locus §The BCL-2 gene is now very close to the gene enhancer for antibodies (which is very active in B cells)

8. Under Normal Cell Operation…. BCL-2 is expressed as an integral membrane protein in the ER, nuclear envelope and mitochondria in B cells Internal damage within the cell causes BCL-2 to release proteins which digest structural proteins and chromosomal DNA B cells usually die after a few days in the body, when their job has been done, by apoptosis

9. In cancerous cells… §BCL-2 is produced in very large amounts, in B cells §A protein similar to BCL-2 is produced, and produces another protein that steps up BCL-2 production as well §Both these make the cell much more resistant to apoptosis, as the internal signals cannot be carried out very effectively §The cell can become cancerous when this happens

10. P53- A tumor suppressor §P53 is a protein which is responsible for activating cell death §When a cell is injured, p53 is activated, and in turn causes the activation of the cell’s apoptotic proteins §P53 therefore is a “controller” of abnormal cells, halting their growth and proliferation

11. P53-continued §The gene that codes for p53 is called a tumor-suppressor gene; therefore, a mutation in the p53 gene is called a tumor-suppressor mutation §Mutations in p53 are recessive, so a person must have a mutation in both copies of the gene for the protein to become inactivated §Cells with inactive p53 are unable to perform apoptosis on damaged or “out of control” cells §These types of cells may proliferate and become cancer