ates generated outside the nucleus could result in substantial changes of cell regulation (Hickman and others 1994).

The level of damage and of consequent p53 function plays a major role either in causing cell-cycle delays (through activation of the p21 gene, which blocks cells in the G1 phase) or in initiating apoptosis. Several of the protein complexes involved in DNA breakage and repair interact with p53, including the homologous and nonhomologous recombination complexes, and the transcription-factor component of nucleotide-excision repair, so the action of repair systems leads into the signal-transduction pathways regulated by p53. Mutations in p53 are important events that occur frequently at some stage in tumor progression and are found in over 50% of all human tumors (Greenblatt and others 1994; Hollstein and others 1991). The consequent functional changes alter many facets of cellular and gene regulation. These mutational changes in p53 do not necessarily constitute the first genetic event in carcinogenesis; for example, they can occur early in sunlight-induced skin tumors (Brash and others 1991) but late in colon cancers (Kinzler and Vogelstein 1996). The p53 protein might, in fact, play a multitude of roles in cancer, from the initial response to DNA damage, through tumor initiation and progression, to final malignancy.

Apoptosis—The Undertaker Genes

Cells die by several routes depending on cell and tissue type and on the particular endogenous and exogenous signals experienced. Unrepaired chromosomal damage can cause ''mitotic death'' when cells attempt to divide; massive damage can cause necrosis, with rapid collapse of the nucleus and permeabilization of the membranes; and a regulated cell-suicide process, apoptosis, that involves activation of proteases (caspases) and nucleases that degrade the cell components in a controlled fashion can occur (figure 6.4) (Cohen 1997). Apoptosis is activated by a wide variety of complex interrelated regulatory and signal-transduction pathways initiated by specific cellular signals, by external irradiation, and by endogenous generation of oxidative products. Some of these processes may be markedly nonlinear functions of dose, since apoptosis is a tissue response which eliminates cells that have suffered more than a critical amount of damage.

Apoptosis is an important feature of normal cell and tissue function, especially when tissue remodeling is involved during embryo development, during wound healing, and after exposure to radiation or chemicals. Apoptosis involves a family of specific proteolytic enzymes (caspases) and a specific nuclease that cleaves DNA at internucleosomal sites and produces characteristic DNA fragmentation (Enari and others 1998). Apoptosis is a complex, regulated process that involves both activators and inhibitors. These molecules fine-tune a cell's response to endogenous damage, modify its redox state, and respond to its immediate environment (Enoch and Norbury 1995; Guillouf and others 1995; Kastan

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