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CELL SUICIDE

CELL SUICIDE. Rebecca Paczkowski Megan McEneely Beth Thomas Mark Wilson. ICE-like protease. Protein-cleaving enzyme that structurally resembles the interleukin-1 converting enzyme

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CELL SUICIDE

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  1. CELL SUICIDE Rebecca Paczkowski Megan McEneely Beth Thomas Mark Wilson

  2. ICE-like protease • Protein-cleaving enzyme that structurally resembles the interleukin-1 converting enzyme • Programs cell death by cleaving various other proteins in ways that “lead to destruction of the cell.” Some of these proteins are essential cell components necessary for structural stability. • HIV-infected individuals have a negative reaction to the ICE-like protease if they are on a protease inhibitor. This inhibitor actually encourages cell growth and leads to further infection since cell apoptosis is avoided. • Tumor cells survive by either expressing survival factors or directly “downgrading” apoptosis inducers such as the ICE-like protease. • Image from http://www.chembio.uoguelph.ca/educmat/chm736/apoptotx.htm

  3. FAS • Fas is a cytokine receptor which mediates programmed cell death, or apoptosis. This is imperative for the removal of autoreactive T cells in order to maintain the homeostasis of the immune-system. • The self-association of a conserved cytoplasmic region of Fas known as the death domain is what actually signals cell death. This domain then interacts with another death-domain-containing protein, FADD. • The Fas death domain is 127 amino acid residues long. Its structure consists of 6 antiparallel, amphipathic alpha-helices (purple). • The Fas death domain is 127 amino acid residues long. Its structure consists of 6 antiparallel, amphipathic alpha-helices (purple). • This image was taken from http://www-nmr.cabm.rutgers.edu/~gardino/page37.html

  4. FAS Ligand • The Fas ligand is a death receptor protein which may induce the apoptosis pathway. • When the Fas ligand binds to Fas, the death pathway of the target cell is initiated. • The Fas ligand is from transmembrane proteins of the tumor necrosis factor familyof receptors and ligands. • Engagement of Fas by FasL triggersa cascade of well-characterized intracellular signaling eventsinvolving homophilic associations of the intracellular death domain,formation of the death-inducing signaling complex, and the recruitmentand activation of a cascade of effector caspase proteases. • Image from http://www.critpath.org/aric/library/img011.htm

  5. Required to protect cells from undergoing programmed cell death Ability to rescue pre-B cells from undergoing apoptosis Role in tumorigenesis: mice with BCL-2 transgene formed malignancies From: http://www.bioscience.org/1997/v2/d/fisher/3.htm BASE COUNT 189 a 249 c 257 g 228 t ORIGIN 1 cagcatcgcc gccgccagag gagaaatgtc tgaagtaaga cccctctcca gagacatctt 61 gatggagacc ctcctgtatg agcagctcct ggaacccccg accatggagg ttcttggcat 121 gactgactct gaagaggacc tggaccctat ggaggacttc gattctttgg aatgcatgga 181 gggcagtgac gcattggccc tgcggctggc ctgcatcggg gacgagatgg acgtgagcct 241 cagggccccg cgcctggccc agctctccga ggtggccatg cacagcctgg gtctggcttt 301 catctacgac cagactgagg acatcaggga tgttcttaga agtttcatgg acggtttcac 361 cacacttaag gagaacataa tgaggttctg gagatccccg aaccccgggt cctgggtgtc 421 ctgcgaacag gtgctgctgg cgctgctgct gctgctggcg ctgctgctgc cgctgctcag 481 cgggggcctg cacctgctgc tcaagtgagc ccccggcggc tcaggcgtgg ctggccccac 541 ccccatgacc actgccctga ggtggcggcc tgctgctgtt atctttttaa ctgttttct601 atgatgcctt ttatattaac cccgtgatag tgctggaaca ctgctgaggt tttatactca 661 ggttttttgt ttttttttta ttccagtttt cgttttttct aaaagatgaa ttcctatggc 721 tctgcaattg tcaccggtta actgtggcct gtgcccagga agagccattc actcctgccc 781 ctgcccacac ggcaggtagc agggggagtg ctggtcacac ccctgtgtga tatgtgatgc841 cctcggcaaa gaatctactg gaatagattc cgaggagcag gagtgctcaa taaaatgttg901 gtttccagca aaaaaaaaaa aaa BCL-2 BCL2 bases (From http://www3.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=n&form=6&uid=U34584&dopt=g)

  6. BCL-2 and apoptosis • Theories: • functions in an antioxidant pathway • prevent hypoxia-induced cell death suggesting that they exert their anti-apoptotic activity by a mechanism other than modulation of oxygen free radicals • may be involved in nuclear transport • Bcl-2 family proteins have been found to recruit and interact with several signaling proteins which may regulate their activities. From: http://www.bioscience.org/1997/v2/d/fisher/3.htm Apoptosis (http://www.chembio.uoguelph.ca/educmat/chm736/apoptotx.htm)

  7. P53 - General Information • Protein produced by a tumor suppressor gene. • Half of cancer patients have p53 mutations. More than 51 human tumors carry p53 mutations (70% of colorectal; 50% of lung; 40% of breast). • The normal form halts cell growth, while the mutant spurs abnormal cell growth. • p53 suppresses development of tumors when it actually binds to DNA. • Mutations change the amino acids so that p53 protein no longer combines with DNA. • http://www.det.mun.ca/dcs/courses/biol2040/Cancr4f.html

  8. P53 and Apoptosis • "DNA damage can induce apoptosis in proliferating lymphoid cells via p53-independent mechanisms inhibitable by Bcl-2," Cell, 79:329-39, 1994. • p53 must be functioning for apoptosis to occur when DNA is damaged by radiation during cancer treatment. • If p53 is missing or mutated, apoptosis is inhibited. • The Scientist, Vol:10, #23, p. 15, November 25, 1996

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