FLIP

Acronym for cellular FLICE-inhibitory protein; FLICE is again an acronym for FADD-like IL-1beta-converting enzymes, where FADD in turn is an acronym for Fas-Associated protein with Death Domain FADD is an adaptor molecule that binds to the FAS receptor (=CD95R) and thus initiates the signaling pathway for apoptosis via the death-inducing signaling complex (DISC). cFLIP occupies a key position in the development of white skin cancer. FLIP serves as a switch for two mechanisms: it can prevent apoptosis and suppress an immune response.

Apoptosis is an essential physiological process for the development and cellular homeostasis of any multicellular organism. In the immune system (see immunity below), apoptosis is responsible both for the maintenance of "self-tolerance" and for the elimination of activated lymphocytes (see apoptosis below) to terminate an immune response (see lymphoma T-cell lymphoma - etiology). The cellular FLIP proteins (c-FLIP) intervene in apoptosis at an early stage by preventing the apoptotic signal from being passed on at the death receptor (DISC = death-inducing signaling complex). This makes them potent apoptosis inhibitors and important regulators in apoptotic signal transduction. At DISC, these "initiator caspases" (caspase-8 and -10) are activated by dimerisation. This initiates an intracellular cascade, which eventually leads to the destruction of the cell. The activation of these "initiator caspases" can be inhibited by FLIP. In FLIP, 3 cellular isoforms have been described in human cells in addition to viral homologues:

• c-FLIPlong
• c-FLIPshort
• c-FLIPR.

The development of specific c-FLIP inhibitors could lead to better immunosuppressive drugs with a lower toxicity than for example cyclosporine A. c-FLIP also plays a crucial role in the apoptosis of keratinocytes, see below ( Apoptosis).

1. Shyam M. Kavuri et al. cFLIP isoforms block CD95- and trail death receptor-induced gene induction irrespective of processing of caspase-8 or cFLIP in the death-inducing signalling complex. The Journal of Biological Chemistry 286: 18614-18622,