New Insights into P53 Signalling and Cancer: Implications for Cancer Therapy

Abstract

The tumor suppressor p53 is one of the most highly studied proteins in the field of cancer research because of its role in tumor cell survival and apoptosis. Research over the past three decades has identified p53 as a multifunctional transcription factor, which regulates the expression of >2,500 target genes. p53 impacts myriad, highly diverse cellular processes, including regulation of the cell cycle, maintenance of genomic stability and fidelity, apoptosis, senescence and longevity, metabolism, angiogenesis, cellular differentiation, and the immune response[1]. It is one of the most important and extensively studied tumor suppressors. Approximately half of human cancers have inactivating mutations in the p53 gene (known as TP53 in human) and most of the remaining malignancies deactivate the p53 pathway by increasing inhibitors, reducing its activators or inactivating its downstream targets. Activated by various stresses, including genotoxic damage, hypoxia, heat shock and oncogenic assault, p53 blocks cancer progression by inducing transient or permanent growth arrest, by enabling DNA repair or by activating cellular death programs[2]. In addition to the indisputable importance of p53 as a tumor suppressor, an increasing and sometimes bewildering number of new roles for p53 have recently been reported, including the ability to regulate metabolism, fecundity, and various aspects of differentiation and development[3].It is impossible to cover all aspects of p53-associated biology in one review and so we have reluctantly passed over many fascinating topics and we will focus on current strategies and challenges to restore p53 tumor suppressor function in established tumors and the therapeutic approaches designed to promote ore deliver wild-type p53 function to cancer cells (i.e. adenoviral gene transfer and small molecule activator of p53, to inactivate p53 inhibitors and to restore wild-type function to mutant p53).