Regulation of TNF Receptor-Mediated Apoptosis

Project: Research project

Project Details

Description

TNF binding to its receptor TNFR1 triggers cell survival or cell death but the
mechanisms that determine which of these two divergent responses is triggered remain to
be fully elucidated. One cell death checkpoint is the activation of NF-kappaB
transcription factors and subsequent induction of anti-apoptotic genes to inhibit the
apoptosis pathway. Preliminary studies performed demonstrated the existence of another
cell death checkpoint regulated by lysine 63-linked ubiquitination of RIP1.
Ubiquitination of lysine 377 on RIP1 inhibits TNF-induced apoptosis first through an
NF-kappaB-independent mechanism, and subsequently through an NF-kappaBdependent
mechanism. In contrast, in the absence of ubiquitination, RIP1 serves as a proapoptotic
signaling molecule. Thus, RIP1 is a dual-function molecule that can be either
pro-survival or pro-death depending on its ubiquitination state and thus serves as an NFkappaB-
independent cell death switch early in TNF signaling. This study proposes to
examine how this cell death checkpoint may be regulated. (1) The mechanism by which
ubiquitination of RIP1, or the lack of it, regulates the activation of caspases will be
examined. (2) The contribution by RIP1-binding partners to this checkpoint will also be
tested. (3) Animal models with genetic modifications in this novel cell death checkpoint
will be developed to study the relevance of this checkpoint in immune function. Insights
gained from these studies may lead to the development of pharmacological agents that
can modulate this cell death checkpoint. Such agents may have therapeutic potential in
inflammatory diseases where TNF plays a role.
StatusNot started

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