Signals from neighbouring cells or tissues will instruct a particular cell to proliferate, differentiate into another cell type or to commit suicide by programmed cell death. Figure 10.4 shows that NFKB can play a major role in countering programmed cell death and hence survival of the cell after stimulation of the TNFa pathway. Such a pathway depends upon the activation of NFKB which will activate a variety of anti-apoptopic genes.

The role of ROS in DNA damage has been widely debated (Wiseman and Halliwell, 1996). Whether increasing iron content in various tissues will exacerbate DNA damage is debatable. Our studies of livers from rats iron loaded for four weeks with ferrocene or iron dextran failed to show any modification of DNA bases (Ward et al., 1995). Since iron is carefully sequestered into ferritin and haemosiderin in iron loading-syndromes it is unclear how it might be released to react with DNA. An increased incidence of hepatic carcinoma has been reported in genetic haemochromatosis patients with iron loading thereby indicating that over a period of years modification of DNA may occur. Ultimately DNA damage can lead to a death-inducing signalling complex, Figure 10.5 (Plate 15). Caspases are thought to be the central executioners of the apoptopic pathway (Hengarten, 2000). The Bcl-2 family is also important in the regulation of the cytochrome c pathway across the mitochondrial outer membrane, the Bcl-2 proteins might act by inserting into the outer mitochondrial membrane to form channels or holes by interacting with other proteins or by control homeostasis of mitochondria (reviewed by Hengarten, 2000). The release of cytochome c from the mitochondria is an almost universal feature of apoptopic cell death although apoptosis induced by death receptors often bypasses the mitochondrial pathway.

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