ABSTRACT
KEY WORDS: radiation, DNA damage, nuclear and membrane signalling, cell cycle.
INTRODUCTION
Engagement of the Fas/APO-1 and TNF receptors with their respective ligands FasL and TNF leads to the initiation of apoptosis by a number of transducing molecules some of which have been identified (Stanger et al., 1995; Hsu et al., 1995). After ligand binding or crosslinking of the receptor, activation is initiated by association of FADD/MORT1 (Fasassociated protein with death domain) with a homologous region on the Fas receptor called the death domain (Boldin et al., 1996; Chinnaiyan et al., 1995). In the case of the TNF receptor, association occurs with TRADD (TNF-RI-associated death domain protein) (Boldin et al., 1996), but FADD also associates with this complex at least in some cell types under conditions that lead to apoptosis. Another protein RIP also associates with both receptors and may be processed by one of several other receptor associated proteins (Kischkel et al., 1995). After these initial changes in the death signalling complex, a cysteine protease MACH/FLICE (caspase 8), is activated and since it is capable of activating a series of other caspases by cleavage it has been suggested that it is at the peak of a cascade of activating reactions (Alnemri et al., 1996). The end result is a series of active caspases which are thought to target specific substrates in the cell (Martin and Green, 1996). Of these caspase 3 has been shown to cleave poly (ADP-ribose) polymerase (PARP) (Lazebnik et al., 1994; Fernandez-Alnemri et al., 1995b) the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) (Song et al., 1996) U1-70kDa (Casciola-Rosen et al., 1994) and PKCδ (Emoto et al., 1995). These and several other caspase substrates appear to be key targets in the nucleus, nuclear scaffold, cytoplasm and cytoskeleton during the onset of apoptosis (Nicholson, 1997). In summary, in the case of anti-Fas and TNFmediated apoptosis, a complex series of signalling steps are initiated from the receptor which leads to protease activation, substrate degradation and ultimately apoptosis.
