ABSTRACT
Since its discovery over 30 years ago, the p53 protein has emerged as a key tumor suppressor protein, and beyond doubt, a crucial player in cancer biology. p53 invokes its tumor-suppressive ability by acting as a mediator of various kinds of stress, such as DNA damage, oxidative stress, and oncogene activation (Horn and Vousden 2007). Through its activity as a transcription factor, p53 regulates the expression of various target genes to prevent tumor development, mainly by inducing cell cycle arrest and DNA repair or triggering cell death and senescence to maintain genomic stability (Kastan et al. 1991; Kuerbitz et al. 1992; Clarke et al. 1993; Lowe et al. 1993). Under mild or transient stress conditions, activated p53 targets several genes involved in cell cycle arrest and DNA repair to stop cells from proliferating and allow repair of any damaged DNA, preventing potentially oncogenic mutations from being passed on to the daughter cells. However, when stress-induced DNA damage is too severe to be reparable, p53 initiates programmed cell death/apoptosis and cellular senescence to eliminate or permanently arrest cells, respectively, which may have acquired irreparable and potentially oncogenic mutations. Relevantly, the human p53 gene
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, MA 02129, USA. aEmail: agurkar@partners.org bEmail: kchu1@partners.org cEmail: swlee@partners.org *Corresponding author
(TP53) is frequently mutated or inactivated in more than 50% of human cancers of different types (Olivier et al. 2010; Robles and Harris 2010). In addition, mice with a p53 gene (Trp53) deletion can develop normally, but develop cancer before the age of 6 months (Donehower et al. 1992). Thus, the importance of p53 in the inhibition of tumor development is indisputable, and consequently, p53 was assigned the title of “guardian of the genome” (Lane 1992). Furthermore, discovery and design of compounds that target the p53 pathway has provided a new approach to cancer therapy.
