Protein Regulation of Apoptosis in Relation to Cancer

1. Protein Regulation of Apoptosis in Relation to Cancer Jenn Mann Elizabeth McCauley Mike Powers Courtney Wilson

2. Definition of Apoptosis • A method by which harmful cells kill themselves • “cell suicide” • Cancer is the result of no apoptosis activity. The tumors that make up cancer neglect to sacrifice themselves on cue. Thus, no apoptosis results in a buildup of harmful cells.

3. How Apoptosis Works • Apoptosis takes place in response to chemical signals. The cells break up into pieces and these pieces are packaged up. Macrophages, or “eaters,” engulf the packages and destroy them. • The following proteins are involved: • ICE-like proteins • FAS • FAS ligand • BCL-2 • p53

4. ICE-like proteins • ICE = Interleukin-Converting Enzyme-mediator of apoptosis • BCL-2 over-expression inhibits ICE-like protease activation. • Intracellular acidification triggers apoptosis by directly or indirectly activating ICE-like proteases. • All apoptotic pathways downstream of p53-mediated transcription converge upon the activation of ICE-like proteases.

5. FAS and FAS ligand • The recent identification of the FAS receptor and it’s ligand as a major regulator of both apoptosis and immune function has provided insight into an attractive mechanism of tumor escape from immune clearance. • FAS and FAS ligand are transmembrane proteins of the tumor necrosis factor family of receptors and ligands. • When the FAS ligand binds to FAS, the death pathway of the target cell is initiated. • The FAS/FAS ligand system also plays an important role in (physiological role) the termination of the immune response.

6. (cont.) • FAS is induced on activated T-lymphocytes and targets them for subsequent elimination by FAS ligand expressing cells. • Tumor cells may acquire resistance to FAS-mediated apoptosis by down-regulating FAS expression or secreting decoy receptors to block FAS ligand on activated T-lymphocytes. • Mutations in oncogenes and tumor suppressor genes such as p53 may also interfere with FAS signaling. • FAS-mediated apoptosis requires the activation of a class of cysteine proteases, which include the ICE family.

7. BCL-2 • Proto-oncogene found on chromosome 18 • Facilitates survival of cells in which it is expressed. • Overexpression of BCL-2 in cells can lead to proliferation of those cells and eventually death of a patient if the cells are cancerous. • High levels of the BCL-2 protein protect cells from early death by apoptosis. The BCL-2 protein suppresses apoptosis by preventing the activation of the caspases that carry out the process.

8. p53 • p53 is a tumor suppressor gene which has been mapped to chromosome 17; its activity stops the formation of tumors. • A person need only inherit one functional copy of the gene from their parents to be predisposed to cancer. • Mutations in p53 are found in most tumor types.

9. (cont.) • In the cell, p53 protein binds DNA stimulates another gene to produce a protein called p21 p21 interacts with a cell division-stimulating protein, cdk2 when p21 is complexed with cdk2, the cell cannot pass to the next stage in cell division • Mutated p53 can no longer bind to DNA in an effective way therefore, p21protein is not made available to act as the “stop signal” for cell division cells then divide uncontrollably and form tumors.

10. Recessive ie. p53 tumor suppressor must lose both copies to lose tumor suppression “loss of function” gene Dominant ie. BCL-2 oncogene only have to acquire one mutation to gain function “gain of function” gene Recessive vs. Dominant Disorders

11. References Duke, Ojcius, and Young. “Cell Suicide in Health and Disease.” SCIENTIFIC AMERICAN. December 1996. http://hepatitis-central.com/hcv/hcc/offense.html http://www.stratagene.com/vol11_1/p6-8.htm http://www.ncbi.nlm.nih.gov/disease/p53.html http://www.ucalgary.ca/UofC/eduweb/virtualembryo/death.html http://www.chembio.uoguelph.ca/educmat/chm736/ apoptotx.htm http://www.biologists.org/JCS/110/05/jcs4356.html