The regulation of cellular metabolism by tumor suppressor p53

Tumor suppressor p53 plays a central role in tumor prevention [1-4]. p53 is the most frequently-mutated gene in human tumors; DNA mutations in p53 occur in over 50% of all tumors and almost every type of tumor. Furthermore, it was estimated that p53 signaling is dysfunctional in over 80% of tumors through different mechanisms in addition to p53 mutations [1-5]. For instance, the negative regulators of p53, including MDM2, Pirh2, Cop1, and MDM4, are frequently amplified and/or overexpressed in many tumors, which leads to the dysfunction of p53 signaling [2,6-8]. In cervical cancer with a low mutation rate of p53, p53 is often inactivated and degraded by human papillomavirus E6 protein (HPV-E6) [9]. Disruption of normal p53 function is often a prerequisite for the initiation and/or progression of tumors. In mice, p53 knockout leads to the early development of various tumors, including lymphoma and sarcoma [10,11]. In human beings, Li–Fraumeni syndrome is a rare disease caused by the germline mutations of p53. Li–Fraumeni syndrome patients, who carry a germline heterozygous p53 gene, display a 50% cancer incidence by the age of 30 [12].As a transcription factor, p53 mainly exerts its function in tumor suppression through transcriptional regulation of its target genes [1-4]. In response to a wide variety of intracellular and extracellular stress signals, including DNA damage, hypoxia, nutritional depletion and oncogene activation, p53 is activated primarily through posttranslational modifications, which leads to the increase of p53 protein half-life and therefore p53 protein accumulation in cells. The activated p53 protein then binds to a specific DNA sequence, termed the p53-responsive element, in its target genes to regulate their expression to start various cellular responses. Through these cellular responses, p53 facilitates DNA repair and inhibits the proliferation of cells that could potentially become cancerous. To date, over a hundred of p53 target genes have be