Bio 353 - Apoptosis: A matter of life and death
Fall, 2001
Haverford College
Jenni Punt

Controversies/Issues

Especially cogent/ insightful student commentaries are posted with each controversy (as the class proceeds)

Select from among the following controversies/issues. Papers associated with these issues are available on line (see links) and should include at least one review article, one historical paper and two recent, primary articles associated with the topic described. During your week, you and your team will provide an overview to the class about the basic biology underlying the question and then present the paper(s) that frame or challenge the issue. You must work to involve the entire class and can devise any means to do so. Articles are available on e-reserves.

Issue #1: Is apoptosis reversible? Selected by Anna Baranano and Jeremy Hansen for 9/10/01
It has long been thought that, once initiated, apoptotic signaling pathways result inevitably in death. These papers raise the possibility that this is not true and give prominence to the phagocytic cells that clear apoptotic cells from the body in determining cell fate. W hat do you think? Student Commentaries

Reddien PW, Cameron S, Horvitz HR. Phagocytosis promotes programmed cell death in C. elegans. Nature. 2001 Jul 12;412(6843):198-202.

Hoeppner DJ, Hengartner MO, Schnabel R. Engulfment genes cooperate with ced-3 to promote cell death in Caenorhabditis elegans. Nature. 2001 Jul 12;412(6843):202-6.

Issue #2: How critical are the pro-apoptotic members of the bcl-2 family in regulating apoptosis? Because bcl-2 was the first gene regulating apoptosis to be identified and has homologs in virtually all metazoan species, it has long been considered the prominent player in apoptotic signaling. However, the identification of egl-1 in C. elegans (a BH3 only bcl-2 family member) and results outlined in these papers raise the possibility that we have been looking at the role of the bcl-2 family 'backwards'. What do you think? (And, for the afficionado, why is there no bax homolog in C. elegans?)

Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ. Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science. 2001 Apr 27;292(5517):727-30.

Sanchez I, Yuan J. A convoluted way to die. Neuron. 2001 Mar;29(3):563-6.

Putcha GV, Moulder KL, Golden JP, Bouillet P, Adams JA, Strasser A, Johnson EM. Induction of BIM, a proapoptotic BH3-only BCL-2 family member, is critical for neuronal apoptosis. Neuron. 2001 Mar;29(3):615-28.

Issue #3: Can cells undergo apoptosis in a caspase independent manner? It has always been interesting and mysterious that, when introduced artifically, bax can induce an apoptotic program in yeast, a single cell organism that does not have caspases. In addition, it has always been interesting and mysterious that C.elegans did not seem to initiate the 'canonical' mitochondrial pathway of cell death, leading some to speculate that mitochondria were not important for C.elegans apoptosis. These papers may help clarify both these issues.

Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature. 2001 Jul 5;412(6842):95-9.

Parrish J, Li L, Klotz K, Ledwich D, Wang X, Xue D. Mitochondrial endonuclease G is important for apoptosis in C. elegans. Nature. 2001 Jul 5;412(6842):90-4.

Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CY, Sasaki T, Elia AJ, Cheng HY, Ravagnan L, Ferri KF, Zamzami N, Wakeham A, Hakem R, Yoshida H, Kong YY, Mak TW, Zuniga-Pflucker JC, Kroemer G, Penninger JM. Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature. 2001 Mar 29;410(6828):549-54.

Issue #4: Does fas do more than induce apoptosis? Fas and its associated signaling complex (the DISC) is the prototypic death receptor in the TNF receptor family and is known to regulate death in immune cells. Absence of fas results in overproduction of immune cells and, in some cases, autoimmunity. Although other TNFR family members can clearly regulate not just death, but other events such as inflammation, such dual role has not been comfortably attributed to fas. These papers suggest that fas and its associated DISC can, in fact, induce proliferation - quite a distinct response! What do you think?

Siegmund D, Mauri D, Peters N, Juo P, Thome M, Reichwein M, Blenis J, Scheurich P, Tschopp J, Wajant H. FADD and Caspase-8 mediate up-regulation of c-fos by FasL and TRAIL via a FLIP-regulated pathway. J Biol Chem. 2001 May 30 [epub ahead of print]

Kabra NH, Kang C, Hsing LC, Zhang J, Winoto A. T cell-specific FADD-deficient mice: FADD is required for early T cell development. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6307-12.

Issue #5: How do IAPs work?
IAPs are a newly discovered group of proteins that appear to inhibit caspases directly. How and why they do what they do are controversial. These papers present an apparently contradictory vision of their mechanism of action. Those interested in protein structure may be particularly interested in this debate.

Goyal L. Cell Death Inhibition: Keeping caspases in check. Cell 2001 104: 805-808.

Silke J, Ekert PG, Day CL, Hawkins CJ, Baca M, Chew J, Pakusch M, Verhagen AM, Vaux DL. Direct inhibition of caspase 3 is dispensable for the anti-apoptotic activity of XIAP. EMBO J. 2001 Jun 15;20(12):3114-23.

Suzuki Y, Nakabayashi Y, Nakata K, Reed JC, Takahashi R. X-linked inhibitor of apoptosis protein (xiap) inhibits caspase-3 and -7 in distinct modes. J Biol Chem. 2001 Jul 20;276(29):27058-63.

Issue #6: Does bcl-2 open or close the mitochondrial voltage dependent adenine nucleotide channel (VDAC)? Although bcl-2 was among the very first regulators of apoptosis ever found, the mechanism of its action is still unknown. One of the most prominent research groups in the area presents a cogent argument that bcl-2/bcl-xL permits mitochondria to continue to function even in suboptimal conditions by allowing a large conductance channel in the outer mitochondrial membrane to continue to function. Another group says bcl-2 saves the cell by blocking this conductance capacity. This is an excellent controversy for the biochemically and biophysically inclined.

Vander Heiden MG, Li XX, Gottleib E, Hill RB, Thompson CB, Colombini M. Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane. J Biol Chem. 2001 Jun 1;276(22):19414-9.

Vander Heiden MG, Chandel NS, Schumacker PT, Thompson CB. Bcl-xL prevents cell death following growth factor withdrawal by facilitating mitochondrial ATP/ADP exchange. Mol Cell. 1999 Feb;3(2):159-67.

Shimizu S, Matsuoka Y, Shinohara Y, Yoneda Y, Tsujimoto Y. Essential role of voltage-dependent anion channel in various forms of apoptosis in mammalian cells. J Cell Biol. 2001 Jan 22;152(2):237-50.

Shimizu S, Konishi A, Kodama T, Tsujimoto Y. BH4 domain of antiapoptotic Bcl-2 family members closes voltage-dependent anion channel and inhibits apoptotic mitochondrial changes and cell death. Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3100-5.

Issue #7: Does fas play a role in 'immune privilege'? Some sites in the body seem to be impervious to immune attack. These include the retina, the testes, and to some extent, the brain and the developing fetus. Some investigators have also considered tumors to have such an 'immune privilege', too. When fas/fasL interactions were first described, clever individuals considered the possibility that they may play a role in maintaining immune privilege. These commentaries frame the controversy surrounding this issue and the paper discusses some of the newest findings related to this possibility.

Restifo NP. Not so Fas: Re-evaluating the mechanisms of immune privilege and tumor escape. Nat Med. 2000 May;6(5):493-5.

Restifo NP. Countering the 'counterattack' hypothesis. Nat Med. 2001 Mar;7(3):259.

O'Connell J, Houston A, Bennett MW, O'Sullivan GC, Shanahan F. Immune privilege or inflammation? Insights into the Fas ligand enigma. Nat Med. 2001 Mar;7(3):271-4.

Aoki K, Kurooka M, Chen JJ, Petryniak J, Nabel EG, Nabel GJ. Extracellular matrix interacts with soluble CD95L: retention and enhancement of cytotoxicity. Nat Immunol. 2001 Apr;2(4):333-7.