ABSTRACT
Up to 10% of human proteins bind zinc, making this family the most abundant class of metal-binding proteins in the metazoan proteome (Anzellotti and Farrell 2008; Maret 2008). Zinc plays a particularly dominant role in regulation of gene expression: Nearly one in two transcription factors binds Zn2+ (Andreini et al. 2006; Tupler, Perini, and Green 2001). The p53 tumor suppressor is chief among these in terms of importance to human health. P53 coordinates cell cycle arrest, apoptosis, and senescence pathways in response to DNA damage, oncogenic stress, and other genomic threats. Not surprisingly, loss of p53 function is associated with many forms of cancer. It was documented 20 years ago that half of human tumors harbor mutations in the p53 gene, establishing p53 as the single most frequently altered protein in cancer (Nigro et al. 1989). More recently, two studies sequenced over 20,000 protein-coding genes from 24 pancreatic tumors (Jones et al. 2008) and 22 glioblastoma multiforme tumors (Parsons et al. 2008) and identified p53 missense mutations as being among the most frequent genomic alterations that allow these cells to escape growth control. Each p53 monomer binds a single zinc ion, which is essential for DNA binding and transcription activation. As we will discuss, a substantial body of in vitro and in vivo evidence indicates that loss of Zn2+ as well as Zn2+-misligation play major roles in loss of p53 function and likely contribute to development of cancer.
