Strategies for manipulating the p53 pathway in the treatment of human cancer

Abstract

Human cancer progression is driven in part by the mutation of oncogenes and tumour-suppressor genes which, under selective environmental pressures, give rise to evolving populations of biochemically altered cells with enhanced tumorigenic and metastatic potential. Given that human cancers are biologically and pathologically quite distinct, it has been quite surprising that a common event, perturbation of the p53 pathway, occurs in most if not all types of human cancers. The central role of p53 as a tumour-suppressor protein has fuelled interest in defining its mechanism of function and regulation, determining how its inactivation facilitates cancer progression, and exploring the possibility of restoring p53 function for therapeutic benefit. This review will highlight the key biochemical properties of p53 protein that affect its tumour-suppressor function and the experimental strategies that have been developed for the re-activation of the p53 pathway in cancers.

Cell shrinkage as a signal to apoptosis in NIH 3T3 fibroblasts

“…The multifunctional transcription factor p53 is a tumour suppressor that has various defects in many cancer cells (Bargonetti & Manfredi, 2002). The activity of p53 is regulated by serine/threonine phosphorylation and by lysine acetylation (Hupp et al 2000). p38, which was found to be activated after cell shrinkage in NIH 3T3 fibroblasts in the present investigation, is known to activate p53 (Sanchez‐Prieto et al 2000; She et al 2001; Kim et al 2002; Zhu et al 2002).…”

Chemotherapeutic Targeting of p53

“…[5][6][7][8][9] The implication is that certain drugs might alter the mutant conformation to force the protein into a more functional or pseudo-wild-type conformation. [10][11][12] The adoption of a normal or near-normal conformation might restore at least some tumor suppressor functions. If drugs that modify p53 conformation can rescue the mutant alleles, then the apoptotic or cytostatic responses associated with functional p53 may be induced.…”

Mutants of the tumour suppressor p53 L1 loop as second-site suppressors for restoring DNA binding to oncogenic p53 mutations: structural and biochemical insights

“…The p53 tumour suppressor protein is a key regulator of the signalling pathways implicated in tumorigenesis and presents a classic example of one of the most prevalently mutated proteins in human cancer. In response to various stress stimuli, p53 activates a network of genes involved in cell cycle arrest, apoptosis and other vital biological processes [1,2]. In the majority of human cancers, p53 function is abrogated either due to mutations in p53 or elsewhere in the p53 signalling pathway.…”

“…Importantly, the p53 mutational status has been associated with poor prognoses in a range of human cancers [3] and p53 is the most commonly mutated gene in breast and colon cancers [4]. Given that p53 is implicated in over 50% of all human cancers, it is not surprising that identifying strategies for restoring function to cancercausing p53 mutations has attracted great interest [1,2,[5][6][7][8]. The inherent complexities of the p53 functions are reflected in the intrinsic structural organisation of the protein.…”