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Ligation of Fas and Cell Death

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The TNF response, NF-kappa B and Bcl-2

28 June 2000

Tomas Jelinek

Homologous to the Fas pathway is the tumor necrosis factor (TNF)-alpha pathway, using many of the same intracellular effectors that are used by Fas. Yet the work of Baltimore, and Baldwin, suggests that what determines whether TNF- stimulated cells undergo apoptosis or proliferation depends on NF-kappa B, a transcription factor. Any effects of NF-kappa B are of necessity delayed by an hour or so, until transcription and translation of target genes can occur. Among those targets are anti-apoptotic Bcl-family members.

Figuring out how this works mechanistically and kinetically should shed light on the question of Bcl-2 inhibition of the Caspase-8 signal. Specific questions:

1. What is the time-course of activation of the various caspases following Fas (or TNF) administration?

2. When NF-kappa B is involved, what is the time-to-appearance of elevated anti-apoptotic proteins on the mitochondria? Is this time shorter than what is seen for Caspase 9 activation in the absence of NF-kappa B?

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