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Ligation of Fas and Cell Death

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The Middle Ground

20 June 2000

Guy Salvesen

David Vaux raised an issue that has become religious in its intensity in the apoptosis field. People like to take sides, and as usual the answer is probably somewhere in the middle. I guess David’s question is "where is the middle"?

A contemporary view of apoptotic signaling defines the "Bcl-2- inhibitable pathway" as the "Intrinsic Apoptotic Pathway" and the "Fas- triggered pathway" as a subset of the death receptor, or "Extrinsic Apoptotic Pathway". I’m not sure when these definitions were suggested, but you can find them in (1).

Both pathways are thought to converge at the activation of pro- caspase-3. Therefore, it would seem that the activation of pro-caspase-3 by caspase-8 of the Extrinsic Pathway is more efficient than sending a signal through the mitochondrial Intrinsic route. Which is easier (more logical)? To cut a piece of string with some scissors that are already at hand; or to cut a rope binding someone so they can go to the hardware store to buy the scissors, get them home to you so you can cut the string?

Key players in the Intrinsic Pathway are the apical caspase-9 whose activation is initiated by its co-factor Apaf-1, following release of cytochrome-C from mitochondria (2). Both Apaf-1 and cytochrome-C seem to be obligatory for the activation of caspase-9 (3, 4), so one can predict that mice ablated in these genes should not be able to support the Intrinsic Pathway. This is indeed the case. Though there are minor differences in apoptotic phenotype, caspase-9 knockouts (5, 6), the Apaf-1 knockout (7, 8), and the cytochrome-C knockout (9) are unable to support apoptosis triggered by Intrinsic Pathway stimuli such as ionizing radiation and cytotoxic drugs. On the other hand all of these knockouts show unimpaired apoptosis via Extrinsic Pathway triggers such as TNF. Indeed the TNF response of embryonic cells in the cytochrome-C knockout is reportedly enhanced (9)! The simplest explanation is that the Intrinsic Pathway is not required in these cases when the trigger is TNF: the Extrinsic Pathway does not need help from the Intrinsic.

Therefore, the apparent requirement of the Intrinsic Pathway in those several cellular and in vivo paradigms (alluded to in David’s post) where the initial trigger is through the Extrinsic Pathway is probably telling us that we are missing something. Something is binding the scissors. Something is putting the breaks on caspase-8, or more likely or caspase-3, in these cells. The "something" should be an additional pro-apoptotic factor that only the Intrinsic Pathway can elaborate, and it should take the breaks off. Since the major difference between the pathways is the requirement of protein flux from mitochondria, then this factor should reside there. Is it AIF (10), or does it await discovery?

The field has come a long way in revealing the key players: the framework of apoptosis. But it’s abundantly clear that many cell types respond differently to the same trigger. Therefore, placed on the framework is a level of control and sophistication that allows precise regulation of death decisions. This is the middle ground, and understanding the cell-specific controls is probably where the future of the field lies. For those of religious fervor on the Bcl- 2/Fas/Extrinsic/Intrinsic questions… Remember – "God is in the details".

REFERENCES

1. Stennicke, H. R., and Salvesen, G. S. (2000) Caspases - controlling intracellular signals by protease zymogen activation. Biochim Biophys Acta 1477, 299-306. [Medline]

2. Li, P. et al. (1997) Cytochrome c and dATP-Dependent Formation of Apaf- 1/Caspase-9 Complex Initiates an Apoptotic Protease Cascade. Cell 91, 479- 489. [Medline]

3. Stennicke, H. R. et al. (1999) Caspase-9 can be activated without proteolytic processing. J Biol Chem 274, 8359-8362.[Abstract/Full Text]

4. Rodriguez, J., and Lazebnik, Y. (1999) Caspase-9 and APAF-1 form an active holoenzyme. Genes Dev 13, 3179-84.[Abstract/Full Text]

5. Kuida, K. et al. (1998) Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94, 325-37. [Medline]

6. Hakem, R. et al. (1998) Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94, 339-52. [Medline]

7. Yoshida, H. et al. (1998) Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94, 739-50. [Medline]

8. Cecconi, F. et al. (1998) Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94, 727-37. [Medline]

9. Li, K. et al. (2000) Cytochrome c deficiency causes embryonic lethality and attenuates stress-induced apoptosis. Cell 101, 389-99. [Medline]

10. Susin, S. A. et al. (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397, 441-6. [Medline]

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