The p53 tumor suppressor is well known as the major target of mutation in human cancers and plays a primary role in protecting cells in the face of genotoxic stresses and challenges to genomic stability. The principal responsibilities of p53 include regulation of genes that promote either arrest of cell cycle or apoptosis, both of which inhibit cellular propagation of DNA damage and tumor development [1-3]. The gene encoding human p53 (TP53) is mutated in more than 50% of all types of human cancers; however, studies of tumor progression in the liver show that mutation of TP53, in the absence of environmental influences discussed below, is a relatively late event in development of hepatocellular carcinoma (HCC) and other cancers of this tissue . In this chapter, we will discuss multiple ways in which dysfunction in p53-signaling occurs, even when TP53 itself is not mutated, in relationship with the biology of p53, its protein domains and specific functions, the influ-ences of p53-family members, and cross-talk with other signaling pathways.
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