Apoptosis in Cancer

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. • 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